Tryptase inhibitors

ABSTRACT

The invention relates to novel inhibitors of human tryptase which are used in the pharmaceutical industry for the production of medicaments.

APPLICATION OF THE INVENTION

The invention relates to novel inhibitors of human tryptase which areused in the pharmaceutical industry for the production of medicaments.

KNOWN TECHNICAL BACKGROUND

Human tryptase is a serine proteinase which is the predominant proteinpresent in human mast cells. The term tryptase covers four closelyrelated enzymes (α, I, II/β, III; possessing 90 to 98% sequenceidentity) (cf. Miller et al., J. Clin. Invest. 84 (1989) 1188-1195;Miller et al., J. Clin. Invest. 86 (1990) 864-870; Vanderslice et al.,Proc. Natl. Acad. Sci., USA 87 (1990) 3811-3815). With the exception ofα-tryptase (Schwartz et al., J. Clin. Invest. 96 (1995) 2702-2710; Sakaiet al., J. Clin. Invest. 97 (1996) 988-995), the enzymes are activatedintracellularly and stored in catalytically active form in secretorygranules.

As compared with other known serine proteinases, such as trypsin orchymotrypsin, tryptase exhibits some exceptional properties (Schwartz etal., Methods Enzymol. 244, (1994), 88-100; G. H. Caughey, “Mast cellproteases in immunology and biology.” Marcel Dekker, Inc., New York,1995). Tryptase obtained from human tissue has a noncovalently linkedtetrameric structure which has to be stabilized by heparin or otherproteoglycans in order to be proteolytically active.

Low-molecular-weight compounds are described as tryptase inhibitors inthe international applications WO 95/32945, WO 96/09297 and WO 98/04537.

DESCRIPTION OF THE INVENTION

It has now been found that the compounds of the formula I described inmore detail below possess surprising and particularly advantageousproperties.

The invention relates to compounds of the formula I

in which

A1 and A2 are identical or different and are —C(O)—, —NH—, —O— (oxygen),—S— (sulfur), —S(O)₂—, —S(O)₂—NH—, —NH—S(O)₂—, —C(O)—NH—, —NH—C(O)—,—O—C(O)—, —C(O)—O— or a bond,

A3 and A4 are identical or different and are —C(O)—, —C(S)—, —O—, —S—,—NH—, —O—C(O)—, —C(O)—O—, —C(O)—NH—, —NH—C(O)— or a bond, or areselected from the group

where

U is —O— (oxygen) or —CH₂— (methylene),

V is —O— (oxygen), —S— (sulfur) or —CH₂— (methylene), and

W is the group —C(O)— or a bond,

A5 and A6 are identical or different and are —C(O)—, —NH—, —O—, —S—,—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,

M is selected from one of the following groups

where

R1 and R2 are identical or different and are hydrogen, 1-4C-alkyl,1-4C-alkyl which is wholly or partially substituted by fluorine, orhydroxyl, or R1 and R2 together, and including the carbon atom to whichthey are bonded, are —C(O)— or a 5- or 6-membered, optionallysubstituted cyclic hydrocarbon,

R3 and R4 are identical or different and are hydrogen or one, two orthree identical or different 1-4C-alkyl radicals,

E is —CH₂—, —O— or a bond,

G is —S—, —O— or —S(O)₂—,

T is —CH₂—, —O— or a bond,

R5 and R6 are identical or different and are hydrogen or 1-4C-alkyl,

R7 is hydrogen, 1-4C-alkyl, phenyl or pyridyl,

R8 is 1-4C-alkoxy, N(R81)R82, piperidino or morpholino,

R81 and R82 are identical or different and are hydrogen or 1-4C-alkyl,

R9 is hydrogen or one, two or three identical or different 1-4C-alkylradicals,

n is 0, 1, 2 or 3,

K1 is -B7-(C(O))_(m)-B9-X1, -B7-(C(O))_(m)-B9-Y1 or-B7-(C(O))_(m)-B9-Z1-B11-X1,

K2 is -B8-(C(O))_(p)-B10-X2, -B8-(C(O))_(p)-B10-Y2 or-B8-(C(O))_(p)-B10-Z2-B12-X2,

B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or1-4C-alkylene,

B7, B8, B9, B10, B11 and B12 are identical or different and are a bondor 1-3C-alkylene,

m is 0 or 1,

p is 0 or 1,

X1 and X2 are identical or different and selected from the followinggroups

where

R10 is 1-4C-alkyl,

Y1 and Y2 are identical or different and are a 4-11C-heteroaryl or2-7C-heterocycloalkyl radical which contains at least one ring nitrogen,

Z1 and Z2 are identical or different and are 5-12C-arylene,5-12C-heteroarylene, 3-8C-cycloalkylene or 3-8C-heterocycloalkylene,

with each arylene, heteroarylene, cycloalkylene, heterocycloalkylene,heteroaryl or heterocycloalkyl additionally, for its part, being able tobe substituted by one, two or three substituents selected from the grouphydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl, 1-4C-alkoxy,1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl or aminocarbonyl,

and in which 24 to 40 bonds must be present on the direct route betweenthe terminal nitrogen atoms, the salts of these compounds, and also theN-oxides of the heteroaryls, heterocycloalkyls, heteroarylenes andheterocycloalkylenes which contain a nitrogen atom, and their salts,

with all those compounds being excluded in which one or more of thevariables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume themeaning of a bond, with this thereby resulting in the direct linkage oftwo heteroatoms, two carbonyl groups or one carbonyl group and onethiocarbonyl group.

1-4C-Alkyl represents straight-chain or branched alkyl radicals havingfrom 1 to 4 carbon atoms. The butyl, the iso-butyl, the sec-butyl, thetert-butyl, the propyl, the isopropyl, the ethyl and the methyl radicalmay be mentioned by way of example.

Examples of 1-4C-alkyl which is entirely or partially substituted byfluorine which may be mentioned are the 2,2,3,3,3-pentafluoropropyl, theperfluoroethyl, the 1,2,2-trifluoroethyl, the 1,1,2,2-tetrafluoroethyl,the 2,2,2-trifluoroethyl, the trifluoromethyl and the difluoromethylradicals.

Examples of a 5- or 6-membered cyclic hydrocarbon which may be mentionedare cyclopentane or cyclohexane.

1-4C-Alkoxy represents radicals which, in addition to the oxygen atom,contain a straight-chain or branched alkyl radical having from 1 to 4carbon atoms. The butoxy, the iso-butoxy, the sec-butoxy, thetert-butoxy, the propoxy, the isopropoxy and, preferably, the ethoxy andthe methoxy radical may be mentioned by way of example.

1-4C-Alkylene represents straight-chain or branched 1-4C-alkyleneradicals, for example the methylene [—CH₂—], the ethylene [—CH₂—CH₂—],the trimethylene [—CH₂—CH₂—CH₂—], the tetramethylene[—CH₂—CH₂—CH₂—CH₂—], the 1,2-dimethylethylene [—CH(CH₃)—CH(CH₃)—], the1,1-dimethylethylene [—C(CH₃)₂—CH₂—], the 2,2-dimethylethylene[—CH₂—C(CH₃)₂—], the isopropylidene [—C(CH₃)₂—] or the 1-methylethylene[—CH(CH₃)—CH₂—] radical.

1-3C-Alkylene represents straight-chain or branched 1-3C-alkyleneradicals, for example the methylene [—CH₂—], the ethylene [—CH₂—CH₂—],the trimethylene [—CH₂—CH₂—CH₂—], the isopropylidene [—C(CH₃)₂—] or the1-methylethylene [—CH(CH₃)—CH₂—] radical.

If m has the meaning 0, the group —(C(O))_(m)— is then a bond.

If p has the meaning 0, the group —(C(O))_(p)— is then a bond.

If n has the meaning 0, the group —(CH₂)_(n)— is then a bond.

4-11C-Heteroaryl is an optionally substituted monocyclic or bicyclicaromatic hydrocarbon which contains from 4 to 11 C atoms and at leastone ring nitrogen atom; in addition, one or more of the carbon atoms canbe replaced by ring heteroatoms selected from the group O, N or S. Inbicycles, at least one of the rings is aromatic. Pyrid-4-yl, pyrid-3-yl,pyrimidin-5-yl, imidazol-1-yl and benzimidazol-5-yl may be mentioned byway of example.

2-7C-Heterocycloalkyl is an optionally substituted monocyclic saturatedor partially saturated hydrocarbon which contains from 2 to 7 C atomsand at least one ring nitrogen atom; in addition, one or more carbonatoms can be replaced by ring heteroatoms selected from the group O, Nor S. Piperid-4-yl, piperazin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl andmorpholin-2-yl may be mentioned by way of example.

5-12C-Arylene is an optionally substituted divalent monocyclic orbicyclic aromatic hydrocarbon radical which possesses from 5 to 12 Catoms, with at least one of the rings being aromatic in the case of thebicyclic aromatic hydrocarbon radicals. The free valencies can both belocated on the aromatic ring or on the nonaromatic ring, or one can belocated on the aromatic ring and one on the nonaromatic ring.1,4-Phenylene, 1,3-phenylene, 1,4-naphthylene and 2,6-naphthylene may bementioned by way of example.

5-12C-Heteroarylene is an arylene radical, as previously defined, inwhich from 1 to 4 C atoms are replaced by heteroatoms selected from thegroup O, N and S. 2,5-Furylene, 2,5-pyrrolylene, 4,2-pyridylene,5,2-pyridylene, 2,5-indolylene, 2,6-indolylene, 3,5-indolylene,3,6-indolylene, 3,5-indazolylene, 3,6-indazolylene, 2,5-benzofuranylene,2,6-quinolinylene and 4,2-thiazolylene may be mentioned by way ofexample.

3-8C-Cycloalkylene is an, optionally substituted, divalent monocyclicsaturated or partially saturated hydrocarbon radical which possessesfrom 3 to 8 C atoms. The 1,3-cyclopentylene, the 1,3-cyclohexylene and,preferably, the 1,4-cyclohexylene radical may be mentioned by way ofexample.

3-8C-Heterocycloalkylene is a cycloalkylene radical, as previouslydefined, in which from 1 to 3 C atoms are replaced by heteroatomsselected from the group O, N and S. The 1,4-piperidinylene, the1,4-piperazinylene, the 2,5-pyrrolidinylene, the 4,2-imidazolidinyleneand, preferably, the 4,1-piperidinylene radical may be mentioned by wayof example.

1-4C-Alkoxycarbonyl is a carbonyl group to which one of theabovementioned 1-4C-alkoxy radicals is bonded. The methoxycarbonyl(CH₃O—C(O)—) and the ethoxycarbonyl (CH₃CH₂O—C(O)—) radical may bementioned by way of example.

1-4C-Alkylcarbonyloxy is a carbonyloxy group to which one of theabovementioned 1-4C-alkyl radicals is bonded. The acetoxy radical(CH₃C(O)—O—) may be mentioned by way of example.

Several of the groups listed under M possess, either in themselves ordue to their substitution, one or more chiral centers. The inventiontherefore encompasses both all the pure enantiomers and all the purediastereomers and also their mixtures in any mixing ratio.

The groups Z1 and Z2, respectively, are located, by definition, betweenthe groups B9 and B11 (-B9-Z1-B11-) and B10 and B12 (-B10-Z2-B12-),respectively. Correspondingly, in the divalent groups (e.g.2,6-indolylene) which are mentioned by way of example, the first numberis that of the site for linkage to the B9 or B10 group, respectively,and the second number is that of the site for linkage to the B11 or B12group, respectively.

In the context of this application, the expression “terminal nitrogenatom” in each case refers to a nitrogen atom in the groups denoted X1,X2, Y1 and Y2.

If the groups X1 and/or X2 contain only one nitrogen atom, this nitrogenatom is the terminal nitrogen atom.

If the groups X1 and/or X2 contain a plurality of nitrogen atoms, thenitrogen atom which is located furthest from the atom via which the bondto groups B9 (B11) or B10 (B12) is effected is the terminal nitrogenatom.

If the groups Y1 and/or Y2 contain only one ring nitrogen atom, thisring nitrogen atom is the terminal nitrogen atom.

If the groups Y1 and/or Y2 contain a plurality of ring nitrogen atoms,the ring nitrogen atom which is located furthest from the atom via whichthe bond with the groups B9 or B10 is effected is the terminal nitrogenatom.

According to the invention, the direct route between the nitrogen atomswhich act as terminal nitrogen atoms in the groups defined as X1 (Y1) orX2 (Y2) is the number of bonds which is obtained by counting the bondswhich represent the shortest possible link between the terminal nitrogenatoms.

The following example is used to illustrate how the number of bonds onthe direct route between two terminal nitrogen atoms is determined:

Here, the direct route encompasses 26 bonds.

The inhibitors according to the invention are bifunctional inhibitors,i.e. inhibitors having two reactive functional groups. These groups aresuch that they can bind specifically to active sites of tryptase. Thetwo functional groups of the inhibitor preferably bind to active sitesin different monomer subunits of the tryptase tetramer.

The inhibitors according to the invention are suitable for inhibitinghuman tryptase. Human tryptase is understood as meaning, in particular,the human enzyme β-tryptase with the EC No. 3.4.21.59.

Depending on substitution, all acid addition salts or all salts withbases are suitable salts for compounds of the formula I. Those which mayin particular be mentioned are the pharmacologically tolerated salts ofthe inorganic and organic acids which are customarily used in pharmacy.Suitable salts of this nature are, on the one hand, water-soluble andwater-insoluble acid addition salts with acids such as hydrochloricacid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid,acetic acid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonicacid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, with the acidsbeing employed, when preparing the salt, in an equimolar quantity ratioor in a quantity ratio which differs from this depending on whether theacid is a monobasic or polybasic acid and on which salt is desired.

On the other hand, salts with bases are also suitable. Examples of saltswith bases which may be mentioned are alkali (lithium, sodium orpotassium) or calcium, aluminum, magnesium, titanium, ammonium, megluminor guanidinium salts, with the bases also in this case being employed,when preparing the salt, in an equimolar quantity ratio, or in aquantity ratio which differs from this.

Salts which are not pharmacologically tolerated and which can, forexample, initially arise as process products when producing thecompounds according to the invention on an industrial scale, areconverted into pharmacologically tolerated salts using methods known tothe skilled person.

The skilled person knows that the compounds according to the invention,and also their salts, when they are isolated in crystalline form, forexample, can contain varying quantities of solvents. The inventiontherefore also encompasses all solvates and, in particular, all hydratesof the compounds of the formula I, as well as all solvates and, inparticular, all hydrates of the salts of the compounds of the formula I.

One embodiment (embodiment a) of the compounds according to theinvention of the formula I is that in which

A1 and A2 are identical or different and are —C(O)—, —NH—, —O— (oxygen),—S— (sulfur), —S(O)₂—, —S(O)₂—NH—, —NH—S(O)₂—, —C(O)—NH—, —NH—C(O)—,—O—C(O)—, —C(O)—O— or a bond,

A3 and A4 are identical or different and are —C(O)—, —C(S)—, —O— —S—,—NH—, —O—C(O)—, —C(O)—O—, —C(O)—NH—, —NH—C(O)— or a bond, or areselected from the group

where

U is —O— (oxygen) or —CH₂— (methylene),

V is —O— (oxygen), —S— (sulfur) or —CH₂— (methylene), and

W is the group —C(O)— or a bond,

A5 and A6 are identical or different and are —C(O)—, —NH—, —O—, —S—,—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,

M is selected from one of the following groups

where

R1 and R2 are identical or different and are hydrogen, 1-4C-alkyl,1-4C-alkyl which is wholly or partially substituted by fluorine, orhydroxyl, or R1 and R2 together, and including the carbon atom to whichthey are bonded, are —C(O)— or a 5- or 6-membered, optionallysubstituted cyclic hydrocarbon,

R3 and R4 are identical or different and are hydrogen or one, two orthree identical or different 1-4C-alkyl radicals,

E is —CH₂—, —O— or a bond,

G is —S—, —O— or —S(O)₂—,

R8 is 1-4C-alkoxy, N(81)R82, piperidino or morpholino,

R81 and R82 are identical or different and are hydrogen or 1-4C-alkyl,

K1 is -B7-(C(O))_(m)-B9-X1, -B7-(C(O))_(m)-B9-Y1 or-B7-(C(O))_(m)-B9-Z1-B11-X1,

K2 is -B8-(C(O))_(p)-B10-X2, -B8-(C(O))_(p)-B10-Y2 or-B8-(C(O))_(p)-B10-Z2-B12-X2,

B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or1-4C-alkylene,

B7, B8, B9, B10, B11 and B12 are identical or different and are a bondor 1-3C-alkylene,

m is 0 or 1,

p is 0 or 1,

X1 and X2 are identical or different and are selected from the followinggroups

where

R10 is 1-4C-alkyl,

Y1 and Y2 are identical or different and are a 4-11C-heteroaryl or2-7C-heterocycloalkyl radical which contains at least one ring nitrogen,

Z1 and Z2 are identical or different and are 5-12C-arylene,5-12C-heteroarylene, 3-8C-cycloalkylene or 3-8C-heterocycloalkylene,

with each arylene, heteroarylene, cycloalkylene, heterocycloalkylene,heteroaryl or heterocycloalkyl additionally, for its part, being able tobe substituted by one, two or three substituents selected from the grouphydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl, 1-4C-alkoxy,1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl or aminocarbonyl,

and in which 24 to 40 bonds must be present on the direct route betweenthe terminal nitrogen atoms,

the salts of these compounds, and also the N-oxides of the heteroaryls,heterocycloalkyls, heteroarylenes and heterocycloalkylenes which containa nitrogen atom, and their salts,

with all those compounds being excluded in which one or more of thevariables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume themeaning of a bond, with this thereby resulting in the direct linkage oftwo heteroatoms, two carbonyl groups or one carbonyl group and onethiocarbonyl group.

Compounds of embodiment a which are to be emphasized are those in which

A1 and A2 are identical or different and are —C(O)—, —NH—, —O— (oxygen),—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,

A3 and A4 are identical or different and are —C(O)—, —O—, —NH—,—O—C(O)—, —C(O)—O—, —C(O)—NH—, —NH—C(O)— or a bond, or are selected fromthe group

where

W is the group —C(O)— or a bond,

A5 and A6 are identical or different and are —C(O)—, —NH—, —O—,—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,

M is selected from one of the following groups

where

R1 and R2 are identical or different and are hydrogen, 1-4C-alkyl,1-4C-alkyl which is wholly or partially substituted by fluorine, orhydroxyl, or R1 and R2 together, and including the carbon atom to whichthey are bonded, are —C(O)— or a 5- or 6-membered, optionallysubstituted cyclic hydrocarbon,

R3 and R4 are identical or different and are hydrogen or one, two orthree identical or different 1-4C-alkyl radicals,

E is —CH₂—, —O— or a bond,

G is —S—, —O— or —S(O)₂—,

R8 is 1-4C-alkoxy, N(R81)R82, piperidino or morpholino,

R81 and R82 are identical or different and are hydrogen or 1-4C-alkyl,

K1 is -B7-(C(O))_(m)-B9-X1, -B7-(C(O))_(m)-B9-Y1 or-B7-(C(O))_(m)-B9-Z1-B11-X1,

K2 is -B8-(C(O))_(p)-B10-X2, -B8-(C(O))_(p)-B10-Y2 or-B8-(C(O))_(p)-B10-Z2-B12-X2,

B1, B2, B3, B4, B5 and B6 are identical or different and are a bond orstraight-chain or branched 1-4C-alkylene,

B7, B8, B9, B10, B11 and B12 are identical or different and are a bondor 1-3C-alkylene,

m is 0 or 1,

p is 0 or 1,

X1 and X2 are identical or different and are selected from the followinggroups

Y1 and Y2 are identical or different and are piperid-4-yl, piperid-3-yl,piperazin-1-yl, piperazin-2-yl, morpholin-2-yl, pyrrolidin-2-yl,pyrrolidin-3-yl, imidazolidin-1-yl, imidazolidin-2-yl,imidazolidin-4-yl, 2-imidazolin-3-yl, 2-imidazolin-2-yl, imidazol-1-yl,imidazol-2-yl, imidazol-4-yl, 5-methylimidazol-4-yl, pyrid-4-yl,pyrid-3-yl, pyridazin-4-yl, pyrimidin-5-yl, pyrimidin-4-yl, indol-3-yl,benzimidazol-4-yl or benzimidazol-5-yl,

Z1 and Z2 are identical or different and are 1,4-phenylene,1,3-phenylene, 1,4-naphthylene, 2,6-naphthylene, 1,4-cyclohexylene,1,3-cyclohexylene, 1,3-cyclopentylene, 1,4-piperazinylene,4,1-piperidinylene, 1,4-piperidinylene, 2,5-pyrrolidinylene,4,2-imidazolidinylene, 2,5-furylene, 2,5-pyrrolylene, 4,2-pyridylene,5,2-pyridylene, 6-methyl-5,2-pyridinylene, 2,5-indolylene,2,6-indolylene, 3,5-indolylene, 3,6-indolylene, 3,5-indazolylene, 3,6-indazolylene, 2, 6-quinolinylene, 2,5-benzofuranylene or4,2-thiazolylene,

and in which 24 to 40 bonds must be present on the direct route betweenthe terminal nitrogen atoms,

the salts of these compounds, and also the N-oxides of the heteroaryls,heterocycloalkyls, heteroarylenes and heterocycloalkylenes which containa nitrogen atom, and their salts,

with all those compounds being excluded in which one or more of thevariables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume themeaning of a bond, with this thereby resulting in the direct linkage oftwo heteroatoms or carbonyl groups.

Compounds of embodiment a which are in particular to be emphasized arethose in which

A1 and A2 are identical or different and are —O— (oxygen) or —NH—C(O)—,

A3 and A4 are identical or different and are —C(O)-NH— or are selectedfrom the group

where W is the group —C(O)— or a bond,

A5 and A6 are identical or different and are —C(O)—, —C(O)—NH—,—NH—C(O)— or a bond,

M is selected from one of the following groups

K1 is -B7-(C(O))_(m)-B9-X1 or -B7-(C(O))_(m)-B9-Z1-B11-X1,

K2 is -B8-(C(O))_(p)-B10-X2 or -B8-(C(O))_(p)-B10-Z2-B12-X2,

B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or—CH₂— (methylene),

B7, B8, B9, B10, B11 and B12 are identical or different and are a bondor 1-2C-alkylene,

m is 0 or 1,

p is 0 or 1,

X1 and X2 are identical or different and are amino, amidino orguanidino,

Z1 and Z2 are identical or different and are 1,4-phenylene,1,3-phenylene, 1,4-cyclohexylene or 1,4-piperazinylene,

and in which 24 to 40 bonds must be present on the direct route betweenthe terminal nitrogen atoms,

the salts of these compounds, with all those compounds being excluded inwhich one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9,B10, B11 or B12 assume the meaning of a bond, with this therebyresulting in the direct linkage of two heteroatoms or two carbonylgroups.

Preferred compounds of embodiment a are those in which

A1 and A2 are identical or different and are —O— (oxygen) or —NH—C(O)—,

A3 and A4 are identical or different and are —C(O)-NH— or are selectedfrom the group

where W is the group —C(O)— or a bond,

A5 and A6 are identical or different and are —C(O)—, —NH—C(O)— or abond,

M is selected from one of the following groups

K1 is -B7-(C(O))_(m)-B9-Z1-B11-X1,

K2 is -B8-(C(O))_(p)-B10-Z2-B12-X2,

B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or—CH₂— (methylene),

B7, B8, B9, B10, B11 and B12 are identical or different and are a bondor —CH₂— (methylene),

m is 0 or 1,

p is 0 or 1,

X1 and X2 are identical or different and are amino, amidino orguanidino,

Z1 and Z2 are identical or different and are 1,4-phenylene,1,3-phenylene, 1,4-cyclohexylene or 1,4-piperazinylene,

and in which 24 to 40 bonds must be present on the direct route betweenthe terminal nitrogen atoms,

the salts of these compounds, with all those compounds being excluded inwhich one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9,B10, B11 or B12 assume the meaning of a bond, with this therebyresulting in the direct linkage of two heteroatoms or two carbonylgroups.

Particularly preferred compounds of embodiment a arebis{4-[4-(4-aminomethylcyclohexanoyl)piperazin-1-yl]-carbonyl}-4,4′-diaminodiphenylether,bis{4-[(3-aminomethyl)benzoylpiperazin-1-yl]carbonyl}-4,4′-diaminodiphenylether,di{4-[4-(4-aminomethyl)cyclohexanoyl-amino]piperidin-1-ylcarbamoyl}cyclohexylmethane,2,2-bis[4-(4-guanidinylbenzylamino)carbonylmethoxyphenyl]-propane,2,2-bis[4-(10-amino-3,6-diaza-2,5-dioxodecyloxyphenyl] propane and2,2-bis{4-[4-(4-aminomethylbenzylcarbamoyl)-1-piperazinylcarbonyloxy]phenyl}propane,and also the salts of these compounds.

Another embodiment (embodiment b) of the compounds according to theinvention of the formula I is that in which

A1 and A2 are identical or different and are —C(O)—, —NH—, —O— (oxygen),—S— (sulfur), —S(O)₂—, —S(O)₂—NH—, —NH—S(O)₂—, —C(O)—NH—, —NH—C(O)—,—O—C(O)—, —C(O)—O- or a bond,

A3 and A4 are identical or different and are —C(O)—, —C(S)—, —O—, —S—,—NH—, —O—C(O)—, —C(O)—O—, —C(O)—NH—, —NH—C(O)— or a bond, or areselected from the group

where

U is —O— (oxygen) or —CH₂— (methylene),

V is —O— (oxygen), —S— (sulfur) or —CH₂— (methylene), and

W is the group —C(O)— or a bond,

A5 and A6 are identical or different and are —C(O)—, —NH—, —O—, —S—,—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,

M is selected from one of the following groups

where

R1 and R2 are identical or different and are hydrogen, 1-4C-alkyl,1-4C-alkyl which is wholly or partially substituted by fluorine, orhydroxyl, or R1 and R2 together, and including the carbon atom to whichthey are bonded, are —C(O)— or a 5- or 6-membered, optionallysubstituted cyclic hydrocarbon,

R3 and R4 are identical or different and are hydrogen or one, two orthree identical or different 1-4C-alkyl radicals,

E is —CH₂—, —O— or a bond,

G is —S—, —O— or —S(O)₂—,

T is —CH₂—, —O— or a bond,

R5 and R6 are identical or different and are hydrogen or 1-4C-alkyl,

R7 is hydrogen, 1-4C-alkyl, phenyl or pyridyl,

R9 is hydrogen or one, two or three identical or different 1-4C-alkylradicals,

n is 0, 1, 2 or 3,

K1 is -B7-(C(O)) B9-X1, -B7-(C(O))_(m)-B9-Y1 or-B7-(C(O))_(m)-B9-Z1-B11-X1,

K2 is -B8-(C(O))_(p)-B10-X2, -B8-(C(O))_(p)-B10-Y2 or-B8-(C(O))_(p)-B10-Z2-B12-X2,

B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or1-4C-alkylene,

B7, B8, B9, B10, B11 and B12 are identical or different and are a bondor 1-3C-alkylene,

m is 0 or 1,

p is 0 or 1,

X1 and X2 are identical or different and selected from the followinggroups

where

R10 is 1-4C-alkyl,

Y1 and Y2 are identical or different and are a 4-11C-heteroaryl or2-7C-heterocycloalkyl radical which contains at least one ring nitrogen,

Z1 and Z2 are identical or different and are 5-12C-arylene,5-12C-heteroarylene, 3-8C-cycloalkylene or 3-8C-heterocycloalkylene,

with each arylene, heteroarylene, cycloalkylene, heterocycloalkylene,heteroaryl or heterocycloalkyl additionally, for its part, being able tobe substituted by one, two or three substituents selected from the grouphydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl, 1-4C-alkoxy,1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl or aminocarbonyl,

and in which 24 to 40 bonds must be present on the direct route betweenthe terminal nitrogen atoms,

the salts of these compounds, and also the N-oxides of the heteroaryls,heterocycloalkyls, heteroarylenes and heterocycloalkylenes which containa nitrogen atom, and their salts,

with all those compounds being excluded in which one or more of thevariables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume themeaning of a bond, with this thereby resulting in the direct linkage oftwo heteroatoms, two carbonyl groups or one carbonyl group and onethiocarbonyl group.

Compounds of embodiment b which are to be emphasized are, on the onehand, those in which

A1 and A2 are identical or different and are —C(O)—, —NH—, —O— (oxygen),—S— (sulfur), —S(O)₂—, —S(O)₂—NH—, —NH—S(O)₂—, —C(O).—NH—, —NH—C(O)—,—O—C(O)—, —C(O)—O— or a bond,

A3 and A4 are identical or different and are —C(O)—, —C(S)—, —O—, —S—,—NH—, —O—C(O)—, —C(O)—O—, —C(O)—NH—, —NH—C(O)— or a bond, or areselected from the group

where

U is —O— (oxygen) or —CH₂— (methylene),

V is —O— (oxygen), —S— (sulfur) or —CH₂— (methylene), and

W is the group —C(O)— or a bond,

A5 and A6 are identical or different and are —C(O)—, —NH—, —O—, —S—,—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,

M is selected from one of the following groups

where

R1 and R2 are identical or different and are 1-4C-alkyl which is whollyor partially substituted by fluorine, or R1 and R2 together, andincluding the carbon atom to which they are bonded, are a 5- or6-membered, optionally substituted cyclic hydrocarbon,

R3 and R4 are identical or different and are hydrogen or one, two orthree identical or different 1-4C-alkyl radicals,

E is —CH₂—, —O— or a bond,

G is —S(O)₂—,

T is —CH₂—, —O— or a bond,

R5 and R6 are identical or different and are hydrogen or 1-4C-alkyl,

R7 is pyridyl,

K1 is -B7-(C(O)) -B9-X1, -B7-(C(O))_(m)-B9-Y1 or-B7-(C(O))_(m)-B9-Z1-B11-X1,

K2 is -B8-(C(O))_(p)-B10-X2, -B8-(C(O))_(p)-B10-Y2 or-B8-(C(O))_(p)-B10-Z2-B12-X2,

B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or1-4C-alkylene,

B7, B8, B9, B10, B11 and B12 are identical or different and are a bondor 1-3C-alkylene,

m is 0 or 1,

p is 0 or 1,

X1 and X2 are identical or different and are selected from the followinggroups

where

R10 is 1-4C-alkyl,

Y1 and Y2 are identical or different and are a 4-11C-heteroaryl or2-7C-heterocycloalkyl radical which contains at least one ring nitrogen,

Z1 and Z2 are identical or different and are 5-12C-arylene,5-12C-heteroarylene, 3-8C-cycloalkylene or 3-8C-heterocycloalkylene,

with each arylene, heteroarylene, cycloalkylene, heterocycloalkylene,heteroaryl or heterocycloalkyl additionally, for its part, being able tobe substituted by one, two or three substituents selected from the grouphydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl, 1-4C-alkoxy,1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl or aminocarbonyl,

and in which 24 to 40 bonds must be present on the direct route betweenthe terminal nitrogen atoms,

the salts of these compounds, and also the N-oxides of the heteroaryls,heterocycloalkyls, heteroarylenes and heterocycloalkylenes which containa nitrogen atom, and their salts,

with all those compounds being excluded in which one or more of thevariables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume themeaning of a bond, with this thereby resulting in the direct linkage oftwo heteroatoms, two carbonyl groups or one carbonyl group and onethiocarbonyl group.

On the other hand, compounds of embodiment b which are to be emphasizedare those in which

A1 and A2 are identical or different and are —C(O)—, —NH—, —O— (oxygen),—S— (sulfur), —S(O)₂—, —S(O)₂—NH—, —NH—S(O)₂—, —C(O)—NH—, —NH—C(O)—,—O—C(O)—, —C(O)—O— or a bond,

A3 and A4 are identical or different and are —C(O)—, —C(S)—, —O—, —S—,—NH—, —O—C(O)—, —C(O)—O—, —C(O)—NH—, —NH—C(O)— or a bond, or areselected from the group

where

U is —O— (oxygen) or —CH₂— (methylene),

V is —O— (oxygen), —S— (sulfur) or —CH₂— (methylene), and

W is the group —C(O)— or a bond,

A5 and A6 are identical or different and are —C(O)—, —NH—, —O—, —S—,—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,

M is selected from one of the following groups

where

R1 and R2 are identical or different and are 1-4C-alkyl or together, andincluding the carbon atom to which they are bonded, are carbonyl,

R3 and R4 are identical or different and are hydrogen or one, two orthree identical or different1-4C-alkyl radicals,

E is —CH₂—, —O— or a bond,

G is —O— (oxygen) or —S— (sulfur),

T is —CH₂—, —O— or a bond,

R5 and R6 are identical or different and are hydrogen or 1-4C-alkyl,

R7 is hydrogen, 1-4C-alkyl or phenyl,

K1 is -B7-(C(O) )_(m)-B9-X1, -B7-(C(O))_(m)-B9-Y1 or-B7-(C(O))_(m)-B9-Z1-B11-X1,

K2 is -B8-(C(O))_(p)-B10-X2, -B8-(C(O))_(p)-B10-Y2 or-B8-(C(O))_(p)-B10-Z2-B12-X2,

B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or1-4C-alkylene,

B7, B8, B9, B10, B11 and B12 are identical or different and are a bondor 1-3C-alkylene,

m is 0 or 1,

p is 0 or 1,

X1 and X2 are identical or different and are selected from the followinggroups

where

R10 is 1-4C-alkyl,

Y1 and Y2 are identical or different and are pyrrolidin-2-yl,imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyridazin-4-yl,indol-3-yl or morpholin-2-yl,

Z1 and Z2 are identical or different and are 5-12C-arylene,5-12C-heteroarylene, 3-8C-cycloalkylene or 3-8C-heterocycloalkylene,

with each arylene, heteroarylene, cycloalkylene, heterocycloalkylene,heteroaryl or heterocycloalkyl additionally, for its part, being able tobe substituted by one, two or three substituents selected from the grouphydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl, 1-4C-alkoxy,1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl or aminocarbonyl,

and in which 24 to 40 bonds must be present on the direct route betweenthe terminal nitrogen atoms,

the salts of these compounds, and also the N-oxides of the heteroaryls,heterocycloalkyls, heteroarylenes and heterocycloalkylenes which containa nitrogen atom, and their salts,

with all those compounds being excluded in which one or more of thevariables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume themeaning of a bond, with this thereby resulting in the direct linkage oftwo heteroatoms, two carbonyl groups or one carbonyl group and onethiocarbonyl group.

Compounds of embodiment b which are furthermore to be emphasized arethose in which

A1 and A2 are identical or different and are —C(O)—, —NH—, —O— (oxygen),—S— (sulfur)—, —S(O)₂—, —NH—S(O)₂—, —S(O)2—NH—, —NH—S(O)₂—, —C(O)—NH—,—NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,

A3 and A4 are identical or different and are —C(O)—, —C(S)—, —O—, —S—,—NH—, —O—C(O)—, —C(O)—O—, —C(O)—NH—, —NH—C(O)— or a bond, or areselected from the group

where

U is —O— (oxygen) or —CH₂— (methylene),

V is —O— (oxygen), —S— (sulfur) or —CH₂— (methylene), and

W is the group —C(O)— or a bond,

A5 and A6 are identical or different and are —C(O)—, —NH—, —O—, —S—,—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,

M is selected from one of the following groups

where

R3 and R4 are identical or different and are hydrogen or one, two orthree identical or different 1-4C-alkyl radicals,

R9 is hydrogen or one, two or three identical or different 1-4C-alkylradicals,

n is 0, 1, 2 or 3,

K1 is -B7-(C(O))_(m)-B9-X1, -B7-(C(O))_(m)-B9-Y1 or -B7- (C(O))_(m)-B9-Z1-B11-X1,

K2 is -B8-(C(O))_(p)-B10-X2, -B8-(C(O))_(p)-B10-Y2 or-B8-(C(O))_(p)-B10-Z2-B12-X2,

B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or1-4C-alkylene,

B7, B8, B9, B10, B11 and B12 are identical or different and are a bondor 1-3C-alkylene,

m is 0 or 1,

p is 0 or 1,

X1 and X2 are identical or different and are selected from the followinggroups

where

R10 is 1-4C-alkyl

Y1 and Y2 are identical or different and are pyrrolidin-2-yl,imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyridazin-4-yl,indol-3-yl or morpholin-2-yl,

Z1 and Z2 are identical or different and are 5-12C-arylene,5-12C-heteroarylene, 3-8C-cycloalkylene or 3-8C-heterocycloalkylene,

with each arylene, heteroarylene, cycloalkylene, heterocycloalkylene,heteroaryl or heterocycloalkyl additionally, for its part, being able tobe substituted by one, two or three substituents selected from the grouphydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl, 1-4C-alkoxy,1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl or aminocarbonyl,

and in which 24 to 40 bonds must be present on the direct route betweenthe terminal nitrogen atoms,

the salts of these compounds, and also the N-oxides of the heteroaryls,heterocycloalkyls, heteroarylenes and heterocycloalkylenes which containa nitrogen atom, and their salts,

with all those compounds being excluded in which one or more of thevariables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume themeaning of a bond, with this thereby resulting in the direct linkage oftwo heteroatoms, two carbonyl groups or one carbonyl group and onethioncarbonyl group.

Compounds of embodiment b which are in particular to be emphasized are,on the one hand, those in which

A1 and A2 are identical or different and are —C(O)—, —NH—, —O— (oxygen),—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,

A3 and A4 are identical or different and are —C(O)—, —O—, —NH—,—O—C(O)—, —C(O)—O—, —C(O)—NH—, —NH—C(O)— or a bond, or are selected fromthe group

where

W is the group —C(O)— or a bond,

A5 and A6 are identical or different and are —C(O)—, —NH—, —O—,—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,

M is selected from one of the following groups

where

R1 and R2 are identical or different and are 1-4C-alkyl which is whollyor partially substituted by fluorine, or R1 and R2 together, andincluding the carbon atom to which they are bonded, are a 5- or6-membered, optionally substituted cyclic hydrocarbon,

R3 and R4 are identical or different and are hydrogen or one, two orthree identical or different 1-4C-alkyl radicals,

E is —CH₂—, —O— or a bond,

G is —S(O)₂—,

T is —CH₂—, —O— or a bond,

R5 and R6 are identical or different and are hydrogen or 1-4C-alkyl,

R7 is pyridyl,

K1 is -B7-(C(O))_(m)-B9-X1, -B7-(C(O))_(m)-B9-Y1 or-B7-(C(O))_(m)-B9-Z1-B11-X1,

K2 is -B8-(C(O))_(p)-B10-X2, -B8-(C(O))_(p)-B10-Y2 or-B8-(C(O))_(p)-B10-Z2-B12-X2,

B1, B2, B3, B4, B5 and B6 are identical or different and are a bondor1-4C-alkylene,

B7, B8, B9, B10, B11 and B12 are identical or different and are a bondor 1-3C-alkylene,

m is 0 or 1,

p is 0 or 1,

X1 and X2 are identical or different and are selected from the followinggroups

Y1 and Y2 are identical or different and are piperid-4-yl, piperid-3-yl,piperazin-1-yl, piperazin-2-yl, morpholin-2-yl, pyrrolidin-2-yl,pyrrolidin-3-yl, imidazolidin-1-yl, imidazolidin-2-yl,imidazolidin-4-yl, 2-imidazolin-3-yl, 2-imidazolin-2-yl, imidazol-1-yl,imidazol-2-yl, imidazol-4-yl, 5-methylimidazol-4-yl, pyrid-4-yl,pyrid-3-yl, pyridazin-4-yl, pyrimidin-5-yl, pyrimidin-4-yl, indol-3-yl,benzimidazol-4-yl or benzimidazol-5-yl,

Z1 and Z2 are identical or different and are 1,4-phenylene,1,3-phenylene, 1,4-naphthylene, 2,6-naphthylene, 1,4-cyclohexylene,1,3-cyclohexylene, 1,3-cyclopentylene, 1,4-piperazinylene,4,1-piperidinylene, 1,4-piperidinylene, 2,5-pyrrolidinylene,4,2-imidazolidinylene, 2,5-furylene, 2,5-pyrrolylene, 4,2-pyridylene,5,2-pyridylene, 6-methyl-5,2-pyridinylene, 2,5-indolylene,2,6-indolylene, 3,5-indolylene, 3,6-indolylene, 3,5-indazolylene,3,6-indazolylene, 2,6-quinolinylene, 2,5-benzofuranylene or4,2-thiazolylene,

and in which 24 to 40 bonds must be present on the direct route betweenthe terminal nitrogen atoms,

the salts of these compounds, and also the N-oxides of the heteroaryls,heterocycloalkyls, heteroarylenes and heterocycloalkylenes which containa nitrogen atom, and their salts,

with all those compounds being excluded in which one or more of thevariables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume themeaning of a bond, with this thereby resulting in the direct linkage oftwo heteroatoms or two carbonyl groups.

Compounds of embodiment b which are in particular to be emphasized are,on the other hand, compounds of the formula I in which

A1 and A2 are identical or different and are —C(O)—, —NH—, —O— (oxygen),—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,

A3 and A4 are identical or different and are —C(O)—, —O—, —NH—,—O—C(O)—, —C(O)—O—, —C(O)—NH—, —NH—C(O)— or a bond, or are selected fromthe group

where

W is the group —C(O)— or a bond,

A5 and A6 are identical or different and are —C(O)—, —NH—, —O—,—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,

M is selected from one of the following groups

where

R1 and R2 are identical or different and are 1-4C-alkyl or together, andincluding the carbon atom to which they are bonded, are carbonyl,

R3 and R4 are identical or different and are hydrogen or one, two orthree identical or different 1-4C-alkyl radicals,

E is —CH₂—, —O— or a bond,

G is —O— (oxygen) or —S— (sulfur),

T is —CH₂—, —O— or a bond,

R5 and R6 are identical or different and are hydrogen or 1-4C-alkyl,

R7 is hydrogen, 1-4C-alkyl or phenyl,

K1 is -B7-(C(O))_(m)-B9-X1, -B7-(C(O))_(m)-B9 Y1 or-B7-(C(O))_(m)-B9-Z1-B11-X1,

K2 is -B8-(C(O))_(p)-B10-X2, -B8-(C(O))_(p)-B10-Y2 or-B8-(C(O))_(p)-B10-Z2-B12-X2, B1, B2, B3, B4, B5 and B6 are identical ordifferent and are a bond or 1-4C-alkylene,

B7, B8, B9, B10, B11 and B12 are identical or different and are a bondor 1-3C-alkylene,

m is 0 or 1,

p is 0 or 1,

X1 and X2 are identical or different and are selected from the followinggroups

where

R10 is 1-4C-alkyl, Y1 and Y2 are identical or different and arepyrrolidin-2-yl, imidazolidin-1-yl, imidazolidin-2-yl,imidazolidin-4-yl, pyridazin-4-yl, indol-3-yl or morpholin-2-yl,

Z1 and Z2 are identical or different and are 1,4-phenylene,1,3-phenylene, 1,4-naphthylene, 2,6-naphthylene, 1,4-cyclohexylene,1,3-cyclohexylene, 1,3-cyclopentylene, 1,4-piperazinylene,4,1-piperidinylene, 1,4-piperidinylene, 2,5-pyrrolidinylene,4,2-imidazolidinylene, 2,5-furylene, 2,5-pyrrolylene, 4,2-pyridylene,5,2-pyridylene, 6-methyl-5,2-pyridinylene, 2,5-indolylene,2,6-indolylene, 3,5-indolylene, 3,6-indolylene, 3,5-indazolylene,3,6-indazolylene, 2,6-quinolinylene, 2,5-benzofuranylene or4,2-thiazolylene,

and in which 24 to 40 bonds must be present on the direct route betweenthe terminal nitrogen atoms,

the salts of these compounds, and also the N-oxides of the heteroaryls,heterocycloalkyls, heteroarylenes and heterocycloalkylenes which containa nitrogen atom, and their salts,

with all those compounds being excluded in which one or more of thevariables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume themeaning of a bond, with this thereby resulting in the direct linkage oftwo heteroatoms or two carbonyl groups.

Compounds of embodiment b which are in particular to be emphasized arefurthermore those in which

A1 and A2 are identical or different and are —C(O)—, —NH—, —O— (oxygen),—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,

A3 and A4 are identical or different and are —C(O)—, —O—, —NH—,—O—C(O)—, —C(O)—O—, —C(O)—NH—, —NH—C(O)— or a bond, or are selected fromthe group

where

W is the group —C(O)— or a bond,

A5 and A6 are identical or different and are —C(O)—, —NH—, —O—,—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,

M is selected from one of the following groups

where

R3 and R4 are identical or different and are hydrogen or one, two orthree identical or different 1-4C-alkyl radicals,

R9 is hydrogen or one, two or three identical or different 1-4C-alkylradicals,

n is 0, 1, 2 or 3,

K1 is -B7-(C(O))_(m)-B9-X1, -B7-(C(O))_(m)-B9-Y1 or-B7-(C(O))_(m)-B9-Z1-B11-X1,

K2 is -B8-(C(O))_(p)-B10-X2, -B8-(C(O))_(p)-B10-Y2 or-B8-(C(O))_(p)-B10-Z2-B12-X2,

B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or1-4C-alkylene,

B7, B8, B9, B10, B11 and B12 are identical or different and are a bondor 1-3C-alkylene,

m is 0 or 1,

p is 0 or 1,

X1 and X2 are identical or different and are selected from the followinggroups

where

R10 is 1-4C-alkyl,

Y1 and Y2 are identical or different and are pyrrolidin-2-yl,imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyridazin-4-yl,indol-3-yl or morpholin-2-yl,

Z1 and Z2 are identical or different and are 1,4-phenylene,1,3-phenylene, 1,4-naphthylene, 2,6-naphthylene, 1,4-cyclohexylene,1,3-cyclohexylene, 1,3-cyclopentylene, 1,4-piperazinylene,4,1-piperidinylene, 1,4-piperidinylene, 2,5-pyrrolidinylene,4,2-imidazolidinylene, 2,5-furylene, 2,5-pyrrolylene, 4,2-pyridylene,5,2-pyridylene, 6-methyl-5,2-pyridinylene, 2,5-indolylene,2,6-indolylene, 3,5-indolylene, 3,6-indolylene, 3,5-indazolylene,3,6-indazolylene, 2,6-quinolinylene, 2,5-benzofuranylene or4,2-thiazolylene,

and in which 24 to 40 bonds must be present on the direct route betweenthe terminal nitrogen atoms,

the salts of these compounds, and also the N-oxides of the heteroaryls,heterocycloalkyls, heteroarylenes and heterocycloalkylenes which containa nitrogen atom, and their salts,

with all those compounds being excluded in which one or more of thevariables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume themeaning of a bond, with this thereby resulting in the direct linkage oftwo heteroatoms or two carbonyl groups.

Compounds of embodiment b which are in particular to be emphasized are,in addition,pyridine-2,6-dicarbobis[4-(3-aminomethylbenzoyl)-1-piperazide],pyridine-2,6-dicarbobis[4-(trans-4-aminomethylcyclohexanoyl)-1-piperazide],2,6-dimethyl-4-phenylpyridine-3,5-dicarbobis[4-(3-aminomethylbenzoyl)-1-piperazide],pyridine-2,6-dicarbobis[4-(3-aminomethylbenzoylamino)-1-piperidide] andpyridine-2,6-dicarbobis[4-(4-aminomethylcyclohexylcarbonylamino)-1-piperidide],and also the salts of these compounds.

A further embodiment (embodiment c) of the compounds of the formula I isthat in which

A1 and A2 are identical or different and are —C(O)—, —NH—, —O— (oxygen),—S— (sulfur), —S(O)₂—, —S(O)₂—NH—, —NH—S(O)₂—, —C(O)—NH—, —NH—C(O)—,—O—C(O)—, —C(O)—O— or a bond,

A3 and A4 are identical or different and are —C(O)—, —C(S)—, —O—, —S—,—NH—, —O—C(O)—, —C(O)—O—, —C(O)—NH—, —NH—C(O)— or a bond, or areselected from the group

where

U is —O— (oxygen) or CH₂— (methylene),

V is —O— (oxygen), —S— (sulfur) or —CH₂— (methylene), and

W is the group —C(O)— or a bond,

A5 and A6 are identical or different and are —C(O)—, —NH—, —O—, —S—,—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,

M is selected from one of the following groups

K1 is -B7-(C(O))_(m)-B9-X1, -B7-(C(O))_(m)-B9-Y1 or -B7-(C(O))_(m)-B9-Z1B11 X1,

K2 is -B8-(C(O))_(p)-B10-X2, -B8-(C(O))_(p)-B10-Y2 or-B8-(C(O))_(p)-B10-Z2-B12-X2,

B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or1-4C-alkylene,

B7, B8, B9, B10, B11 and B12 are identical or different and are a bondor 1-3C-alkylene,

m is 0 or 1,

p is 0 or 1,

X1 and X2 are identical or different and are selected from the followinggroups

where

R10 is 1-4C-alkyl,

Y1 and Y2 are identical or different and are a 4-4C-heteroaryl or2-7C-heterocycloalkyl radical which contains at least one ring nitrogen,

Z1 and Z2 are identical or different and are 5-12C-arylene,5-12C-heteroarylene, 3-8C-cycloalkylene or 3-8C-heterocycloalkylene,

with each arylene, heteroarylene, cycloalkylene, heterocycloalkylene,heteroaryl or heterocycloalkyl additionally, for its part, being able tobe substituted by one, two or three substituents selected from the grouphydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl, 1-4C-alkoxy,1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl or aminocarbonyl,

and in which 24 to 40 bonds must be present on the direct route betweenthe terminal nitrogen atoms,

the salts of these compounds, and also the N-oxides of the heteroaryls,heterocycloalkyls, heteroarylenes and heterocycloalkylenes which containa nitrogen atom, and their salts,

with all those compounds being excluded in which one or more of thevariables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume themeaning of a bond, with this thereby resulting in the direct linkage oftwo heteroatoms, two carbonyl groups or one carbonyl group and onethiocarbonyl group.

Compounds of embodiment c which are to be emphasized are those in which

A1 and A2 are identical or different and are —C(O)—, —NH—, —O— (oxygen),—S— (sulfur), —S(O)₂—, —S(O)₂—NH—, —NH—S(O)₂—, —C(O)—NH—, —NH—C(O)—,—O—C(O)—, —C(O)—O— or a bond,

A3 and A4 are identical or different and are —C(O)—, —C(S)—, —O—, —S—,—NH—, —O—C(O)—, —C(O)—O—, —C(O)—NH—, —NH—C(O)— or a bond, or areselected from the group

where

U is —O— (oxygen) or —CH₂— (methylene),

V is —O— (oxygen), —S— (sulfur) or —CH₂— (methylene), and

W is the group —C(O)— or a bond,

A5 and A6 are identical or different and are —C(O)—, —NH—, —O—, —S—,—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,

M is selected from one of the following groups

where

K1 is -B7-(C(O))_(m)-B9-X1, -B7-(C(O))_(m)-B9-Y1 or-B7-(C(O))_(m)-B9-Z1-B11-X1,

K2 is -B8-(C(O))_(p)-B10-X2, -B8-(C(O))_(p)-B10-Y2 or-B8-(C(O))_(p)-B10-Z2-B12-X2,

B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or1-4C-alkylene,

B7, B8, B9, B10, B11 and B12 are identical or different and are a bondor l-3C-alkylene,

m is 0 or 1,

p is 0 or 1,

X1 and X2 are identical or different and are selected from the followinggroups

where

R10 is 1-4C-alkyl,

Y1 and Y2 are identical or different and are pyrrolidin-2-yl,imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyridazin-4-yl,indol-3-yl or morpholin-2-yl,

Z1 and Z2 are identical or different and are 5-12C-arylene,5-12C-heteroarylene, 3-8C-cycloalkylene or 3-8C-heterocycloalkylene,

with each arylene, heteroarylene, cycloalkylene, heterocycloalkylene,heteroaryl or heterocycloalkyl additionally, for its part, being able tobe substituted by one, two or three substituents selected from the grouphydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl, 1-4C-alkoxy,1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl or aminocarbonyl,

and in which 24 to 40 bonds must be present on the direct route betweenthe terminal nitrogen atoms,

the salts of these compounds, and also the N-oxides of the heteroaryls,heterocycloalkyls, heteroarylenes and heterocycloalkylenes which containa nitrogen atom, and their salts,

with all those compounds being excluded in which one or more of thevariables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume themeaning of a bond, with this thereby resulting in the direct linkage oftwo heteroatoms, two carbonyl groups or one carbonyl group and onethiocarbonyl group.

Compounds of embodiment c which are in particular to be emphasized arethose in which

A1 and A2 are identical or different and are —C(O)—, —NH—, —O— (oxygen),—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,

A3 and A4 are identical or different and are —C(O)—, —O—, —NH—,—O—C(O)—, —C(O)—O—, —C(O)—NH—, —NH—C(O)— or a bond, or are selected fromthe group

where

W is the group —C(O)— or a bond,

A5 and A6 are identical or different and are —C(O)—, —NH—, —O—,—C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,

M is selected from one of the following groups

K1 is -B7-(C(O))_(m)-B9-X1, -B7-(C(O))_(m)-B9-Y1 or -B7- (C))_(m)-B9-Z1-B11-X1,

K2 is -B8-(C(O))_(p)-B10-X2, -B8-(C(O))_(p)-B10-Y2 or-B8-(C(O))_(p)-B10-Z2-B12-X2,

B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or1-4C-alkylene,

B7, B8, B9, B10, B11 and B12 are identical or different and are a bondor 1-3C-alkylene,

m is 0 or 1,

p is 0 or 1,

X1 and X2 are identical or different and are selected from the followinggroups

where

R10 is 1-4C-alkyl,

Y1 and Y2 are identical or different and are pyrrolidin-2-yl,imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyridazin-4-yl,indol-3-yl or morpholin-2-yl,

Z1 and Z2 are identical or different and are 1,4-phenylene,1,3-phenylene, 1,4-naphthylene, 2,6-naphthylene, 1,4-cyclohexylene,1,3-cyclohexylene, 1,3-cyclopentylene, 1,4-piperazinylene,4,1-piperidinylene, 1,4-piperidinylene, 2,5-pyrrolidinylene,4,2-imidazolidinylene, 2,5-furylene, 2,5-pyrrolylene, 4,2-pyridylene,5,2-pyridylene, 6-methyl-5,2-pyridinylene, 2,5-indolylene,2,6-indolylene, 3,5-indolylene, 3,6-indolylene, 3,5-indazolylene,3,6-indazolylene, 2,6-quinolinylene, 2,5-benzofuranylene or4,2-thiazolylene,

and in which 24 to 40 bonds must be present on the direct route betweenthe terminal nitrogen atoms,

the salts of these compounds, and also the N-oxides of the heteroaryls,heterocycloalkyls, heteroarylenes and heterocycloalkylenes which containa nitrogen atom, and their salts,

with all those compounds being excluded in which one or more of thevariables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume themeaning of a bond, with this thereby resulting in the direct linkage oftwo heteroatoms or two carbonyl groups.

The compounds of the formula I are composed of a large number ofdivalent building blocks (M, A1, A2, A3, A4, A5, A6, B1, B2, B3, B4, B5,B6, B7, B8, B9, B10, B11, B12, Z1 and Z2). In principle, they can besynthesized starting from any one of these building blocks. In the caseof compounds of the formula I which are constructed to a large extentsymmetrically, preference is given to starting the synthesis with thecentral building block M; by contrast, it can be advantageous tosynthesize compounds of the formula I which are predominantlyasymmetrical starting with one of the end groups K1 or K2.

In this connection, the building blocks are always linked together inaccordance with the same pattern, which is known per se to the skilledperson.

The skilled person knows that the compounds of the formula I can besynthesized building block by building block; alternatively, relativelylarge fragments, consisting of several individual building blocks, canfirst of all be constructed, with these fragments then being assembledinto the whole molecule.

Amino [—NH—], ether [—O—], thioether [—S—], keto [—C(O)—], thioketo[—C(S)—], sulfonyl [—S(O)₂—], ester [—O—C(O)—, —C(O)—O—], amide[—C(O)—NH—, —NH—C(O)—], sulfonamide [—SO₂—NH—, —NH—SO₂—], carbamate[—NH—C(O)—O—, —O—C(O)—NH—], carbamide (—NH—C(O)—NH—) or carbonate[—O—C(O)—O—] bridges occur in the compounds of the formula I as a resultof the meanings which the individual building blocks of the compounds ofthe formula I can assume.

The manner in which such bridges are prepared is known per se to theskilled person, and suitable methods, and starting compounds forpreparing them, are described, for example, in March, Advanced OrganicChemistry, Reactions, Mechanisms and Structure, Third Edition, 1985,John Wiley & Sons.

For example, ether and thioether bridges can be prepared by the methodof Williamson.

Keto or thioketo bridges can, for example, be introduced as componentsof larger building blocks, such as 1,3-dichloroacetone.

Sulfonyl bridges can be obtained, for example, by oxidizing thioetherbridges.

A large number of methods are known for synthesizing ester bridges.Mention may be made here, by way of example, of the reaction of acidswith alcohols, preferably using H₂SO₄ or p-toluenesulfonic acid ascatalyst; or with the addition of a water-extracting agent, such as amolecular sieve or a carbodiimide. The reaction of acid chlorides withalcohols may also be mentioned at this point.

There is also a large number of known methods for preparing amidebridges. The reaction of acid chlorides with primary or secondary aminesmay be mentioned here as an example. In addition, reference may also bemade to all the methods which have been developed for peptide chemistry.Correspondingly, sulfonamide bridges can be synthesized from sulfonylchlorides and primary or secondary amines.

Carbamate bridges can be prepared, for example, by reactingchlorocarbonic esters with amines. The chlorocarbonic esters can, fortheir part, be synthesized from alcohols and phosgene.

The addition of alcohols to isocyanates constitutes another variant forsynthesizing carbamate bridges.

In a similar way to carbamate bridges, carbonate bridges can be preparedfrom chlorocarbonic esters by reacting them with alcohols (instead ofamines).

Carbamide bridges can be prepared, for example, by reacting isocyanateswith amines.

It is also possible to convert compounds of the formula I byderivatization into other compounds of the formula I. Thus, for example,compounds of the formula I which have a nitrogen-containing heteroarylor heterocycloalkyl building block can be converted by oxidation intothe corresponding N-oxides.

The N oxidation is effected in a manner with which the skilled person isalso familiar, for example using hydrogen peroxide in methanol orm-chloroperoxybenzoic acid in dichloromethane at room temperature. Theskilled person is familiar, on the basis of his specialist knowledge,with the detailed reaction conditions which are required for carryingout the method.

It is furthermore known to a person skilled in the art that, if astarting material or intermediate contains a plurality of reactivecenters, it may be required to protect one or more reactive centerstemporarily by protective groups so that a reaction can take placeselectively at the desired reaction center. A detailed description ofhow a large number of proven protective groups are used is given, forexample, in T. W. Greene, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991.

The substances according to the invention are isolated and purified in amanner known per se, for example by the solvent being distilled off invacuo and the resulting residue being recrystallized from a suitablesolvent or being subjected to one of the customary purification methodssuch as column chromatography on a suitable support material.

Salts are obtained by dissolving the free compound in a suitablesolvent, for example in a chlorinated hydrocarbon, such as methylenechloride or chloroform, or a low molecular weight aliphatic alcohol(ethanol, isopropanol), which contains the desired acid or base, or towhich the desired acid or base is subsequently added. The salts areisolated by filtering, reprecipitation or precipitation with a substancewhich does not dissolve the addition salt, or by evaporating off thesolvent. Resulting salts can be converted, by alkalizing or acidifying,into the free compounds, which can be converted into salts once again.In this way, salts which are not tolerated pharmacologically can beconverted into salts which are tolerated pharmacologically.

The preparation of compounds of the formula I may be demonstrated, byway of example, with the aid of the following Examples 1 to 12 and FIGS.1 to 12. Other compounds of the formula I can be prepared analogously orusing the methods which are cited above and which are known per se tothe skilled person.

FIGS. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 show formula schemes forpreparing bifunctional inhibitors according to the invention.

EXAMPLES Example 1 End ProductPyridine-2,6-dicarbobis[4-(3-aminomethylbenzoyl)-1-piperazide] (1) (cf.FIG. 1)

1.3 ml of a 4.8 N solution of HCl in dioxane (6.2 mmol) are addeddropwise to a solution of 600 mg (780 μmol) ofpyridine-2,6-dicarbobis[4-(3-butyloxycarbonylaminomethylbenzoyl)-1-piperazide]in 7 ml of dioxane. 10 ml of methanol are added to the thick suspensionand the mixture is stirred for 2.5 hours. It is then concentrated andthe residue is taken up in 25 ml of water and the solution is adjustedto pH=11 (NaOH). The solution is then extracted with 3×20 ml ofdichloromethane, and the combined organic phases are dried over MgSO₄and concentrated. The product is dissolved in 2 ml of dioxane, with 0.5ml of a 4.8 N solution of HCl in dioxane (2.4 mmol) then being added;the suspension is diluted with 15 ml of diethyl ether. The titlecompound is isolated as hydrochloride having a m.p. of >260° C.

Starting CompoundsPyridine-2,6-dicarbobis[4-(3-tert-butyloxycarbonylaminomethylbenzoyl)-1-piperazide](2)

1.36 ml (9.7 mmol) of triethylamine, 610 mg (2.42 mmol) of3-tert-butyloxycarbonylaminomethylbenzoic acid, 330 mg (2.42 mmol) of1-hydroxybenzotriazole and 460 mg (2.42 mmol) ofN-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC×HCl)are added, one after the other, to a suspension of 500 mg (1.21 mmol) ofpyridine-2,6-dicarbobispiperazide trihydrochloride in 15 ml of DMF.After 75 min., the reaction mixture is extensively concentrated, afterwhich 20 ml of water are added to the residue and the resulting solutionis adjusted to pH=11 (NaOH). It is then extracted with 3×20 ml ofdichloromethane, after which the combined organic phases are dried overMgSO₄ and concentrated, and the crude product is chromatographed throughsilica gel (ethyl acetate/methanol=10:1). The eluate is concentrated andthe residue is stirred thoroughly in diethyl ether. 700 mg (75%) of thetitle compound having a m.p. of 195° C. (frothing at 110° C.) areobtained.

Pyridine-2,6-dicarbobispiperazide (3)

6.8 ml of a 4.8 N solution of HCl in dioxane (16.2 mmol) are addeddropwise to a suspension of 2.05 g (4.07 mmol) ofpyridine-2,6-dicarbobis-4-tert-butyloxycarbonylpiperazide in 20 ml ofdioxane. The suspension is diluted with 10 ml of methanol and themixture is stirred at room temperature overnight. The solvent isextensively concentrated, after which the suspension is thoroughlystirred with diethyl ether and filtered under a protective gasatmosphere. 1.7 g (100%) of the trihydrochloride of the title compoundare obtained. m.p. >260° C.

Pyridine-2,6-dicarbobis-4-tert-butyloxycarbonylpiperazide (4)

1.0 g (5.0 mmol) of 2,6-pyridinedicarbonyl dichloride in 10 ml ofdioxane is added dropwise to a solution of 1.88 g (10.1 mmol) oftert-butyl piperazine-N-carboxylate in 0.82 ml (10.1 mmol) of pyridine,3.5 ml (25.2 mmol) of triethylamine and 10 ml of dioxane. The mixture isstirred at room temperature overnight, after which the precipitate isfiltered off and the mother liquor is concentrated to dryness. Theresidue is extracted with 3×30 ml of dichloromethane from 30 ml ofwater. The organic phase, which has been dried over MgSO₄, isconcentrated and the residue is crystallized from diethyl ether. 2.16 g(90%) of the title compound having a m.p. of 183-186° C. are obtained.

Example 2 End ProductsPyridine-2,6-dicarbobis[4-(trans-4-aminomethylcyclohexanoyl)-1-piperazide](5) (cf. FIG. 2)

1.06 ml of a 4.6 N solution of HCl in dioxane (5.1 mmol) are addeddropwise to a solution of 500 mg (640 μmol) ofpyridine-2,6-dicarbobis[4-(trans-4-tert-butyloxycarbonylaminomethylcyclohexylcarbonyl)-1-piperazide]in 10 ml of dioxane. 20 ml of methanol are added to the thick suspensionand the whole is stirred at 40° C. for 4 hours. The mixture isconcentrated; the residue is then coevaporated with 2×20 ml of tolueneand crystallized from diethyl ether. The title compound is isolated asthe dihydrochloride having a m.p. of 170° C. (frothing).

Example 32,6-Dimethyl-4-phenylpyridine-3,5-dicarbobis[4-(3-aminomethylbenzoyl)-1-piperazide](7) (cf. FIG. 3)

522 μl of a 4.6 N solution of HCl in dioxane (2.4 mmol) are added to asolution of 350 mg (0.4 mmol) of2,6-dimethyl-4-phenylpyridine-3,5-dicarbobis[4-(3-tert-butyloxycarbonylaminomethylbenzoyl)-1-piperazide]in 5 ml of dioxane and 5 ml of methanol. After the mixture has beenstirred overnight at room temperature, a further 200 μl (0.9 mmol) ofHCl in dioxane are added and the reaction mixture is heated at 40° C.for 5 hours. The mixture is concentrated, and the residue is stirred upwith 5 ml of dioxane and 2 ml of diethyl ether, and the title compoundis isolated as dihydrochloride having a m.p. of 250° C. (sintering at223° C.).

Starting CompoundsPyridine-2,6-dicarbobis[4-(trans-4-tert-butyloxycarbonylaminomethylcyclohexylcarbonyl)-1-piperazide](6)

1.36 ml (9.7 mmol) of triethylamine, 620 mg (2.42 mmol) oftrans-4-tert-butyloxycarbonylaminomethylcyclohexane-carboxylic acid, 330mg (2.42 mmol) of 1-hydroxy-benzotriazole and 460 mg (2.42 mmol) ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC×HCl)are added, one after the other, to a suspension of 500 mg (1.21 mmol) ofpyridine-2,6-dicarbobispiperazide trihydrochloride in 15 ml of DMF.After 45 min., the reaction mixture is extensively concentrated, afterwhich 20 ml of water are added to the residue and the resulting solutionis adjusted to pH=12 (NaOH). It is then extracted with 3×20 ml ofdichloromethane, after which the combined organic phases are dried overMgSO₄ and concentrated, and the crude product is chromatographed throughsilica gel (ethyl acetate/methanol/ammonia=10:1:0.5). The eluate isconcentrated and the residue is stirred thoroughly in diisopropyl ether.620 mg (65%) of the title compound, having a m.p. of 200-202° C., areobtained.

2,6-Dimethyl-4-phenylpyridine-3,5-dicarbobis[4-(3-tert-butyloxycarbonylaminomethylbenzoyl)-1-piperazide](8)

500 μl (4.2 mmol) of triethylamine, 280 mg (1.1 mmol) of3-tert-butyloxycarbonylaminomethylbenzoic acid, 280 mg (1.1 mmol) of1-hydroxybenzotriazole and 280 mg (2.1 mmol) ofN-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC×HCl)are added, one after the other, to a suspension of 220 mg (0.53 mmol) of2,6-dimethyl-4-phenylpyridine-3,5-dicarbobispiperazide in 10 ml of DMF.After 4 hours, the reaction mixture is extensively concentrated afterwhich 30 ml of water are added to the residue and the resulting solutionis adjusted to pH=12 (NaOH). It is then extracted with a total of 70 mlof dichloromethane, after which the combined organic phases are driedover MgSO₄ and concentrated, and the crude product is chromatographedthrough silica gel (ethyl acetate/methanol=10:1). The eluate isconcentrated and the residue is stirred thoroughly in diisopropyl ether.446 mg (96%) of the title compound, having a m.p. of 113° C., areobtained.

2,6-Dimethyl-4-phenylpyridine-3,5-dicarbobispiperazide (9)

12.6 ml of a 4.6 N solution of HCl in dioxane (57.6 mmol) are addeddropwise to a suspension of 15 5.87 g (9.6 mmol) of2,6-dimethyl-4-phenylpyridine-3,5-dicarbobis-4-tert-butyloxycarbonylpiperazidein 20 ml of dioxane and 10 ml of methanol. The mixture is stirred atroom temperature for 5 hours. The solvent is concentrated and theresidue is thoroughly stirred with 30 ml of diethyl ether and 70 ml ofmethanol. 4.35 g (94%) of the dihydrochloride of the title compound,having a m.p. of >250° C., are obtained.

2,6-Dimethyl-4-phenylpyridine-3,5-dicarbobis-4-tert-butyloxycarbonylpiperazide(10)

13.0 g (mmol) of dipotassium2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylate are boiled, at 100° C.for 5 hours and under a nitrogen atmosphere, in 80 ml of phosphorusoxychloride. The phosphorus oxychloride is distilled off in vacuo andthe residue is coevaporated with 3×50 ml of toluene. A suspension of acrude acid chloride in 200 ml of dioxane is added dropwise, whilecontrolling the temperature (<30° C.), to a solution of 12.8 g (66 mmol)of tert-butyl piperazine-N-carboxylate, 5.3 ml (66 mmol) of pyridine and46 ml (450 mmol) of triethylamine in 100 ml of dioxane. After one hour,the inorganic salts are filtered off and the filtrate is concentrated.The residue is extracted from 100 ml of water using 3×70 ml of ethylacetate. The combined organic phases, which have been dried over MgSO₄,are concentrated and the residue is chromatographed through silica gel(ethyl acetate/methanol=10:1). 7.13 g (35%) of the title compound areobtained as a yellowish oil.

Example 4 End ProductPyridine-2,6-dicarbobis[4-(3-aminomethylbenzoylamino)-1-piperidide] (11)(cf. FIG. 4)

275 μl of a 4 N solution of HCl in dioxane (1.1 mmol) are added dropwiseto a solution of 220 mg (275 μmol) ofpyridine-2,6-dicarbobis[4-(3-tert-butyloxycarbonylaminomethylbenzoylamino)-1-piperidide]in 5 ml of dioxane. 3 ml of methanol are added to the thick suspensionand the whole is stirred for 12 hours. The mixture is concentrated andthe residue is coevaporated with 2×20 ml of toluene and crystallized.130 mg of the title compound, having a m.p. of 230° C. (frothing), areobtained.

Starting CompoundsPyridine-2,6-dicarbobis[4-(3-tert-butyloxycarbonylaminomethylbenzoylamino)-1-piperidide](12)

342 mg (1.36 mmol) of 3-tert-butyloxycarbonylaminomethylbenzoic acid,240 μl (1.36 mmol) of Hunig's base, 30 mg of diaminopyridine and 260 mg(1.36 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (EDC×HCl) are added, one after the other, to a suspensionof 250 mg (0.62 mmol) of pyridine-2,6-dicarbobis(4-amino-1-piperidide)dihydrochloride in 2.5 ml of DMF and 2.5 ml of dioxane. After havingbeen stirred at room temperature for 12 hours, the reaction mixture isconcentrated, after which 10 ml of water are added to the residue andthe resulting solution is adjusted to pH=3 (0.1 N HCl). It is thenextracted with 3×20 ml of dichloromethane, after which the combinedorganic phases are dried over MgSO₄ and concentrated, and the crudeproduct is chromatographed through silica gel(dichloromethane/methanol=19:1). The product-containing eluate isconcentrated and the residue is thoroughly stirred in diethyl ether. 280mg (57%) of the title compound, having a m.p. of 140° C. (frothing,sintering from 120° C. onward) are obtained.

Pyridine-2,6-dicarbobis(4-amino-1-piperidide) (13)

12 ml of a 6 N solution of HCl in diethyl ether (72 mmol) are addeddropwise to a solution of 2.0 g (3.76 mmol) ofpyridine-2,6-dicarbobis(4-tert-butyloxycarbonylamino-1-piperidide) in 10ml of diethyl ether, 30 ml of methanol and 20 ml of dichloromethane, andthe reaction mixture is heated at 40° C. for 2 hours. The solvent isconcentrated and the residue is thoroughly stirred with diethyl etherand filtered off under a protective gas atmosphere. 1.52 g (100%) of thedihydrochloride of the title compound are obtained. m.p. 130° C.

Pyridine-2,6-dicarbobis(4-tert-butyloxycarbonylamino-1-piperidide) (14)

850 mg (4.05 mmol) of 2,6-pyridinedicarbonyl dichloride in 10 ml ofdioxane are added dropwise to a suspension of 1.67 g (8.08 mmol) oftert-butyl piperidine-N-carboxylate in 0.65 ml (8.08 mmol) of pyridine,2.8 ml (20 mmol) of triethylamine and 10 ml of dioxane. The mixture isstirred overnight at room temperature and then concentrated. 30 ml ofwater are added to the residue and the resulting solution is made basic(pH=11) with NaOH. It is then extracted with 3×30 ml of dichloromethane,after which the combined organic phases are dried over MgSO₄ andconcentrated, and the residue is crystallized from diethyl ether. 2.12 g(99%) of the title compound, having a m.p. of 90° C., are obtained.

Example 5 End ProductPyridine-2,6-dicarbobis[4-(4-aminomethylcyclohexylcarbonylamino)-1-piperidide](15) (cf. FIG. 5)

500 μl of a 4 N solution of HCl in dioxane (2.0 mmol) are added dropwiseto a suspension of 160 mg (197 μmol) ofpyridine-2,6-dicarbobis[4-(4-tert-butyloxycarbonylaminomethylcyclohexylcarbonylamino)-1-piperididein 10 ml of dioxane and 2 ml of methanol, and the mixture is stirred atroom temperature for 12 hours. It is then concentrated and the residueis coevaporated twice with 50 ml of diethyl ether; the crude product isthen thoroughly stirred in diethyl ether. 100 mg of the title compound,having a m.p. of >250° C., are obtained.

Starting CompoundsPyridine-2,6-dicarbobis[4-(4-tert-butyloxycarbonylaminomethylcyclohexylcarbonylamino)-1-piperidide](16)

350 mg (1.36 mmol) oftrans-3-tert-butyloxycarbonylaminomethylcyclohexylcarboxylic acid, 240μl (1.36 mmol) of Hunig's base, 30 mg of diaminopyridine and 260 mg(1.36 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (EDC×HCl) are added, one after the other, to a suspensionof 250 mg (0.62 mmol) of pyridine-2,6-dicarbobis(4-amino-1-piperidide)dihydrochloride in 2.5 ml of DMF and 2.5 ml of dioxane. After havingbeen stirred at room temperature for 12 hours, the reaction mixture isconcentrated, after which 10 ml of water are added to the residue andthe resulting solution is adjusted to pH=3 (0.1 N HCl). It is thenextracted with 3×20 ml of dichloromethane, after which the combinedorganic phases are dried over MgSO₄ and concentrated, and the crudeproduct is chromatographed through silica gel(dichloromethane/methanol=19:1). The product-containing eluate isconcentrated and the residue is thoroughly stirred in diethyl ether. 230mg (46%) of the title compound, having a m.p. of >250° C., are obtained.

Example 6 End ProductBis{4-[4-(4-aminomethyl)cyclohexanoylpiperazin-1-yl]-carbonyl}-4,4′-diaminodiphenylether dihydrochloride (17) (cf. FIG. 6)

Bis{4-[4-(4-tert-butoxycarbonylaminomethyl)cyclohexanoylpiperazin-1-yl]carbonyl}-4,4′-diaminodiphenylether (0.18 g; 0.2 mmol) is suspended in 4.8 M HCl in dioxane (5 ml).The suspension is stirred at 40-45° C. 20 for 24 hours. After theaddition of diethyl ether (25 ml), the mixture is cooled in an ice bath.The product, which has precipitated out, is filtered off with suction,washed several times with diethyl ether and dried in vacuo. Yield: 0.12g, white amorphous solid.

MS (ESI): 703.4 (100) MH⁺

Starting CompoundsBis{4-(4-(4-tert-butoxycarbonylaminomethyl)cyclohexanoylpiperazin-1-yl]carbonyl}-4,4′-diaminodiphenylether (18)

4,4′-Bis(1-piperazinylcarbamoyl)diphenyl ether dihydrochloride (0.25 g;0.5 mmol), Boc-tranexamic acid (0.28 g; 1.1 mmol),N-ethyldiisopropylamine (0.2 ml; 1.1 mmol) and 4-dimethylaminopyridine(5 mg) are stirred, at room temperature for 15 minutes, in dimethylformamide (2.5 ml) and dichloromethane (2.5 ml). After the addition ofN-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (0.21 g;

1.1 mmol), the reaction mixture is stirred at 40° C. for 24 hours. Thesolvent is stripped off completely in vacuo. The residue ischromatographed on silica gel (dichloromethane:methanol —9:1). Theproduct fraction is collected and the solvent is stripped off completelyin vacuo. Yield: 0.18 g, white amorphous solid.

MS (ESI): 903.1 (100) MH⁺

4,4′-Bis(1-piperazinylcarbamoyl)diphenyl ether dihydrochloride (19)

4,4′-Bis[4-(tert-butyloxycarbonyl)-1-piperazinylcarbamoyl]diphenyl ether(6.4 g; 10.2 mmol) is suspended in 4.8 M HCl in dioxane (50 ml). Thesuspension is stirred at 40-45° C. for 22 hours. After the addition ofdiethyl ether (100 ml), the mixture is cooled in an ice bath. Theproduct, which has precipitated out, is filtered off with suction,washed several times with diethyl ether and dried in vacuo. Yield: 4.65g, white amorphous solid.

MS (APCI): 425.0 (100) MH⁺

4,4′-Bis[4-(tert-butyloxycarbonyl)-1-piperazinylcarbamoyl]diphenyl ether(20)

A solution of 4,4′-oxybis(phenyl isocyanate) (2.52 g, 10 mmol) indichloromethane (25 ml) is added dropwise, at room temperature, to astirred solution of 1-tert-butoxycarbonylpiperazine (4.10 g; 22 mmol) indichloromethane (50 ml). After the addition has come to an end, themixture is stirred at room temperature for a further 3 hours. Theproduct, which has precipitated out, is filtered off with suction,washed several times with hexane and dried in vacuo. Yield: 6.20 g of awhite amorphous solid.

MS (EI): 625.5 (12) MH⁺; 271.2 (26); 118.2 (42); 187.1 (100)

Example 7 End ProductBis{4-[4-(3-aminomethyl)benzoylpiperazin-1-yl]-carbonyl}-4,4′-diaminodiphenylether dihydrochloride (21) (cf. FIG. 7)

Bis{4-[4-(3-tert-butoxycarbonylaminomethyl)benzoylpiperazin-1-yl]carbonyl}-4,4′-diaminodiphenylether (0.31 g; 0.35 mmol) is stirred, at 40-45° C. for 24 hours, in 4.8M HCl in dioxane (5 ml). After the addition of diethyl ether (25 ml),the mixture is cooled in an ice bath. The product, which hasprecipitated out, is filtered off with suction, washed several timeswith diethyl ether and dried in vacuo. Yield: 0.19 g, white amorphoussolid.

MS (ESI): 691.2 (100) MH⁺

Starting CompoundsBis{4-[4-(3-tert-butoxycarbonylaminomethyl)benzoylpiperazin-1-yl]carbonyl)}4,4′-diaminodiphenylether (22)

4,4′-Bis(1-piperazinylcarbamoyl)diphenyl ether dihydrochloride (0.25 g;0.5 mmol), 3-(tert-butoxycarbonylaminomethyl)benzoic acid (0.28 g; 1.1mmol), N-ethyl-diisopropylamine (0.2 ml; 1.1 mmol) and4-dimethylaminopyridine (30 mg) are stirred, at room temperature for 15minutes, in dimethyl formamide (2.5 ml) and dioxane (2.5 ml). After theaddition of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(0.21 g; 1.1 mmol), the reaction mixture is stirred at room temperaturefor 24 hours. The solvent is stripped off completely in vacuo. Theresidue is chromatographed on silica gel (dichloromethane:methanol—9:1).The product fraction is collected and the solvent is stripped offcompletely in vacuo. Yield: 0.32 g, viscous oil.

MS (ESI): 890.8, M⁺; 791.2, MH-Boc⁺

Example 8 End ProductDi{4-[4-(4-aminomethyl)cyclohexanoylamino]piperidin-1-ylcarbamoyl}cyclohexylmethanedihydrochloride (23) (cf. FIG. 8)

Di{4-[4-(4-tert-butoxycarbonylaminomethyl)cyclohexanoylamino]piperidin-1-ylcarbamoyl}cyclohexylmethane(0.65 g; 0.7 mmol) is stirred, at 40-45° C. for 24 hours, in 4.8 M HClin dioxane (7 ml). After the addition of diethyl ether (50 ml), themixture is cooled in an ice bath. The product, which has precipitatedout, is filtered off with suction, washed several times with diethylether and dried in vacuo. Yield: 0.26 g, white amorphous solid.

MS (ESI): 741.5 (100) MH⁺

Starting CompoundsDi{4-[4-(4-tert-butoxycarbonylaminomethyl)cyclohexanoylamino]piperidin-1-ylcarbamoyl}cyclohexylmethane(24)

Di [4-(4-aminopiperidin-1-ylcarbamoyl)]cyclohexylmethane dihydrochloride(0.54 g; 1.0 mmol), Boc-tranexamic acid (0.57 g; 2.2 mmol),N-ethyldiisopropylamine (0.38 ml; 2.2 mmol) and 4-dimethylaminopyridine(30 mg) are stirred, at room temperature for 15 minutes, in dimethylformamide (5 ml) and dioxane (5 ml). After the addition of N-(3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (0.43 g; 2.2mmol), the reaction mixture is stirred at 40° C. for 48 hours. Thesolvent is completely stripped off in vacuo. The residue ischromatographed on silica gel (dichloromethane:methanol—9:1). Theproduct fraction is collected and the solvent is stripped off completelyin vacuo. Yield: 0.65 g, viscous oil, which was subjected to furtherreaction without any characterization.

Di[4-(4-aminopiperidin-1-ylcarbamoyl)]cyclohexylmethane dihydrochloride(25)

Di{4-[4-(tert-butoxycarbamoyl)piperidin-1-yl-carbamoyl]}cyclohexylmethane(4.90 g; 7.0 mmol) is suspended in 4.8 M HCl in dioxane (50 ml). Thesuspension is stirred at 40-45° C. for 48 hours. After the addition ofdiethyl ether (100 ml), the mixture is cooled in an ice bath. Theproduct, which has precipitated out, is filtered off with suction,washed several times with diethyl ether and dried in vacuo. Yield: 4.10g, white amorphous solid.

MS(EI): 463.4 (100) MH⁺

Di{4-[4-(tert-butoxycarbamoyl)piperidin-1-yl-carbamoyl]}cyclohexylmethane(26)

A solution of dicyclohexylmethane-4,4′-diisocyanate (1.90 g; 7.3 mmol)in dichloromethane (10 ml) is added dropwise, at room temperature, tothe stirred solution of 4-tert-butoxycarbamoylpiperidine (3.20 g; 16.0mmol) in dichloromethane (30 ml). After the addition has come to an end,the mixture is stirred at room temperature for a further three hours.The product, which has precipitated out, is filtered off with suction,washed several times with hexane and dried in vacua. Yield: 4.10 g,white amorphous solid.

MS(ESI) : 685.3 (57) MNa⁺; 663.2 (100) MH⁺

Example 9 End Product2,2-Bis{4-[4-(4-aminophenyl)-1-piperazinylcarbonylmethoxy]phenyl}propanedihydrochloride (27) (cf. FIG. 9)

0.65 g of2,2-bis{4-[4-(4-nitrophenyl)-1-piperazinylcarbonylmethoxy]phenyl}propaneis dissolved in 60 ml of glacial acetic acid, and 0.2 g of palladiumcharcoal (10%) is added. The mixture is hydrogenated in a bypassapparatus until the starting product can no longer be detected (TLC).The catalyst is filtered off with suction through celite and thefiltrate is evaporated down to dryness in vacuo on a rotary evaporator.The residue is dissolved in dichloromethane and the solution is washedwith NaHCO₃ solution, dried over Na₂SO₄, filtered and concentrated onceagain. The residue is chromatographed through a silica gel column usinga mixture consisting of ethyl acetate/methanol/NH₄OH (25%), in the ratio90:8:2, as the mobile phase. The chromatographically pure fractions arecombined and concentrated, and the residue is dissolved indichloromethane. Following the addition of ethereal hydrochloric acid,the solution is concentrated and the residue is subsequently distilledtwice with dichloromethane and then triturated with ethylacetate/isopropanol. The precipitate is filtered off with suction,washed and then dried under high vacuum. 0.32 g of the title compound,having a m.p., with decomposition, from 182° C., is obtained.

Starting Compounds2,2-Bis{4-[4-(4-nitrophenyl)-1-piperazinylcarbonylmethoxy]phenyl}propane(28)

2.5 g of 4-[4-carboxymethoxyphenyl)-1-methylethyl]-phenoxyacetic acidare suspended in toluene, and 1.6 ml of thionyl chloride are added. Themixture is heated under reflux for 5 hours and, after cooling, isconcentrated on a rotary evaporator. The residue is subsequentlydistilled twice with toluene and the resulting crude diacid chloride isthen dissolved in 50 ml of abs. dioxane. 2.95 g of1-(4-nitrophenyl)piperazine, 2 ml of triethylamine and a spatula tip of4-dimethylaminopyridine are added one after the other. The mixture isstirred at 50° C. for 2.5 h. Following cooling, water is added to themixture and the pH is adjusted to 9 with dilute sodium hydroxidesolution. The product, which has separated out, is caused to crystallizeby grinding, and the crystals are then filtered off with suction, washedwith water and dried over calcium chloride. 4.7 g of the title compound,having a m.p., with decomposition, from 165° C., are obtained.

4-[1-(4-Carboxymethoxyphenyl)-1-methylethyl]phenoxyacetic acid (29)

6.7 g of ethyl4-[1-(4-ethoxycarbonylmethoxyphenyl)-1-methylethyl]phenoxyacetate aredissolved in 20 ml of methanol, and 16.7 g of 10% strength sodiumhydroxide solution are added. The mixture is heated to boiling underreflux for 3 hours, after which it is cooled down and the methanol isthen distilled off on a rotary evaporator. The residue is diluted withwater and acidified to pH 2 with 2 N HCl; the colorless precipitate isthen filtered off with suction, washed with water and dried in vacuoover calcium chloride. 5.5 g of the title compound, having a m.p. of177-179° C., are obtained.

Ethyl 4-[1-(4-ethoxycarbonylmethoxyphenyl)-1-methyl-ethyl]phenoxyacetate(30)

A mixture of 10 g of 4,4′-isopropylidenediphenol, 10.7 ml of ethylbromoacetate, 15.2 g of potassium carbonate and 1 spatula tip of18-crown-6 in 180 ml of acetone is heated to boiling under reflux for 4hours. The solid is then removed by filtering off with suction and thefiltrate is concentrated in vacuo and 100 ml of diisopropyl ether areadded to the residue. The precipitate is filtered off with suction,washed with a little diisopropyl ether and dried. 15.5 g of the titlecompound, having a m.p. of 69-71° C., are obtained.

Example 10 End Product2,2-Bis-[4-(4-guanidinylbenzylamino)carbonylmethoxyphenyl]propanedihydroacetate (31) (cf. FIG. 10)

0.88 g of 1,3-bis(benzyloxycarbonyl)-2-methylisothiourea, 0.68 g ofmercury(II) chloride and 0.69 g of triethylamine are added, one afterthe other, while stirring, to 0.63 g of2,2-bis-[4-(4-aminobenzylamino)-carbonylmethoxyphenyl]propane in 10 mlof abs. DMF. The mixture is stirred at room temperature for 3 h and isthen diluted with ethyl acetate; the precipitate which results isremoved by filtering off with suction and the filtrate is washed oncewith a 5% strength soda solution and twice with water. The solution isdried over magnesium sulfate and filtered with suction, and the filtrateis evaporated to dryness in vacuo. The oil is chromatographed through asilica gel column using a mixture consisting of dichloromethane/ethanol,95:5. The chromatographically pure fractions are combined andconcentrated, and the residue (0.9 g) is dissolved in a mixtureconsisting of 60 ml of tetrahydrofuran, 3 ml of methanol and 1 ml ofglacial acetic acid. After 0.3 g of palladium charcoal (10%) has beenadded, the mixture is hydrogenated in a bypass apparatus until thestarting compound can no longer be detected. The catalyst is removed byfiltering off with suction and the filtrate is evaporated to dryness.The viscous oil which remains is stirred up with THF and the resultingprecipitate is filtered off with suction, washed with THF and diethylether and dried in vacuo at 80° C. 0.35 g of the title compound, havinga m.p. of 135° (decomposition), is obtained.

Starting Compounds2,2-Bis-[4-(4-aminobenzylamino)carbonylmethoxyphenyl]-propane (32)

1.8 g of 2,2-bis-[4-(4-nitrobenzylamino)carbonylmethoxyphenyl]propaneare dissolved in 300 ml of THF and, after addition of 0.5 g of palladiumcharcoal (10%), are hydrogenated in a bypass apparatus until thestarting compound can no longer be detected (TLC). After the catalysthas been filtered off with suction, the filtrate is concentrated todryness in vacuo and the residue is chromatographed through a silica gelcolumn using a mixture of dichloromethane/ethanol, 95:5. Thechromatographically pure fractions are combined and concentrated, andthe residue is dried under high vacuum. 1.05 g of the title compound areobtained in the form of a solidified foam.

2,2-Bis-[4-(4-nitrobenzylamino)carbonylmethoxyphenyl]-propane (33)

1.5 ml of thionyl chloride are added to 2 g of4-[l-(4-carboxymethoxyphenyl)-1-methylethyl]phenoxyacetic acid in 100 mlof toluene, and the mixture is heated to boiling under reflux for 5 h.After cooling, it is concentrated on a rotary evaporator and the residueis subsequently distilled twice with toluene. The resulting diacidchloride is dissolved in 40 ml of abs. dioxane, after which 2.2 g of4-nitrobenzylamine hydrochloride are added; 3.5 ml of triethylamine arethen added dropwise. The mixture is stirred at 50° C. for 2 h and thenconcentrated in vacuo. The precipitate which is obtained after addingwater is filtered off with suction and dried in vacuo and, for furtherpurification, chromatographed through a silica gel column usingethylacetate. The chromatographically pure fractions are combined,concentrated and dried. 1.25 g of the title compound are obtained as asolidified foam.

Example 11 End Product 52,2-Bis-[4-(10-amino-3,6-diaza-2,5-dioxodecyloxy)-phenyl]propanedihydrochloride (34) (cf. FIG. 11)

0.77 g of2,2-bis-{4-[10-(tert-butoxycarbonylamino)-3,6-diaza-2,5-dioxodecyloxy]phenyl}propaneis dissolved in 10 ml of abs. dioxane, and 2 ml of an approx. 4.8 Msolution of hydrogen chloride in dioxane are added to this solution. Themixture is stirred overnight and the resulting precipitate is thenfiltered off with 15 suction, washed with dioxane and then with diethylether and dried in vacuo at 80° C. 0.58 g of the title compound, havinga m.p. of 173° C. (decomposition), is obtained.

Starting Compounds2,2-Bis-[4-(10-(tert-butoxycarbonylamino)-3,6-diaza-2,5-dioxodecyloxy]phenyl}propane(35)

0.67 g of 2,2-bis-(4-chlorocarbonylmethoxyphenyl)-propane (prepared inanalogy with Example 33) in 5 ml of abs. dioxane is added dropwise,while stirring, to a solution of 0.85 g ofN-[4-(tert-butoxycarbonylamino)butyl]glycineamide and 0.42 g oftriethylamine in 10 ml of abs. dioxane. The mixture is stirred overnightand concentrated in vacuo, and the residue is partitioned between waterand ethyl acetate. The organic phase is washed twice with water, driedover magnesium sulfate and concentrated. The residue is chromatographedthrough a silica gel column using a mixture of dichloromethane/ethanol,95:5. The chromatographically pure fractions are combined andconcentrated, and the residue is crystallized using diethylether/2-propanol. It is filtered off with suction, washed with diethylether and dried in vacuo. 0.77 g of the title compound, having a m.p. of59° C. (decomposition), is obtained.

Example 12 End Product2,2-Bis-{4-[4-(4-aminomethylbenzylcarbamoyl)-1-piperazinylcarbonyloxy]phenyl}propanedihydrochloride (36) (cf. FIG. 12)

0.14 g of2,2-bis-{4-[4-(4-tert-butoxycarbonylaminomethylbenzylcarbamoyl)-1-piperazinylcarbonyloxy]-phenyl}propaneis dissolved in 2 ml of abs. dioxane, and 2 ml of an approx. 20%solution of hydrogen chloride in dioxane is added to this solution. Themixture is stirred overnight and the precipitate is filtered off withsuction, washed twice with diethyl ether and dried in vacuo. 0.08 g ofthe title compound, having a m.p. of from 250° C. (decomposition), isobtained.

Starting Compounds2,2-Bis-{4-[4-(4-tert-butoxycarbonylaminomethylbenzylcarbamoyl)-1-piperazinylcarbonyloxy]phenyl}propane(37)

0.2 g of 2,2-bis[4-(1-piperazinylcarbonyloxy)phenyl]-propanedihydrochloride and 0.66 ml of diisopropylethylamine are dissolved in 5ml of dichloromethane, and 0.4 ml of a 20% strength solution of phosgenein toluene is then added to this solution. After the mixture has beenstirred at room temperature for 30 min, 0.18 g of4-(tert-butoxycarbonylaminomethyl)-benzylamine is added and the mixtureis stirred for a further 30 min. Water is then added and the phases areseparated; the organic phase is then washed a further two times withwater. After the organic phase has been dried over magnesium sulfate, itis concentrated on a rotary evaporator. The residue is chromatographedthrough a silica gel column using dichloromethane/methanol, 95:5, as themobile phase. The chromatographically pure fractions are combined andevaporated to dryness in vacuo. 0.17 g of the title compound is obtainedas a solidified foam.

2,2-Bis[4-(1-piperazinylcarbonyloxy)phenyl]propane dihydrochloride (38)

8.3 g of2,2-bis[4-(4-tert-butoxycarbonyl-1-piperazinylcarbonyloxy)phenyl]propanedihydrochloride are dissolved in 50 ml of abs. dioxane, and 9.5 ml of anapprox. 20% solution of hydrogen chloride in dioxane are added to thissolution while stirring. The mixture is stirred overnight, after whichit is diluted with toluene and the precipitate is filtered off withsuction. After drying in vacuo, 5.7 g of the title compound, having am.p. of from 200° C. (decomposition), are obtained.

2,2-Bis[4-(4-tert-butoxycarbonyl-1-piperazinylcarbonyloxy)phenyl]propane(39)

5 g of bisphenol A bis(chloroformate) are dissolved in 50 ml ofdichloromethane, and 7.3 ml of diisopropylethylamine and 6.6 g of1-tert-butoxycarbonylpiperazine are added while cooling with ice. Themixture is stirred at room temperature for 1 h and then extracted threetimes with an ice-cold 0.5 N solution of hydrochloric acid and twicewith 1 N sodium hydroxide solution. After having been dried withmagnesium sulfate, it is then evaporated on a rotary evaporator and thesolid is dried in vacuo. 8.4 g of the title compound, having a m.p. of171-172° C., are obtained.

Commercial Utility

As inhibitors of human tryptase, the compounds according to theinvention have useful pharmacological properties which make themcommercially utilizable. Human tryptase is a serine protease which isthe main protein in human mast cells. Tryptase comprises four closelyrelated enzymes (α, I, II/β, III; 90 to 98% sequence identity) (cf.Miller et al., J. Clin. Invest. 84 (1989) 1188-1195; Miller et al., J.Clin. Invest. 86 (1990) 864-870; Vanderslice et al., Proc. Natl. Acad.Sci., USA 87 (1990) 3811-3815). Except for α-tryptase (Schwartz et al.,J. Clin. Invest. 96 (1995) 2702-2710; Sakai et al., J. Clin. Invest. 97(1996) 988-995) the enzymes are activated intracellularly and stored incatalytically active form in secretory granules. Compared with otherknown serine proteases, such as, for example, trypsin or chymotripsin,tryptase has some special properties (Schwartz et al., Methods Enzymol.244, (1994), 88-100; G. H. Caughey, “Mast cell proteases in immunologyand biology”. Marcel Dekker, Inc. New York, 1995). Tryptase from humantissue has a noncovalently-linked tetrameric structure which has to bestabilized by heparin or other proteoglycanes to be proteolyticallyactive. Together with other inflammatory mediators, such as, forexample, histamine and proteoglycanes, tryptase is released when humanmast cells are activated. Because of this, tryptase is thought to play arole in a number of disorders, in particular in allergic andinflammatory disorders, firstly because of the importance of the mastcells in such disorders and secondly because an increased tryptaseconcentration was observed in a number of disorders of this type. Thus,tryptase is associated, inter alia, with the following diseases; acuteand chronic (in particular inflammatory and allergen-induced) airwaydisorders of various origins (for example bronchitis, allergicbronchitis, bronchial asthma, COPD); interstitial lung disorders;disorders based on allergic reactions of the upper airways (pharynx,nose) and the adjacent regions (for example paranasal sinuses,conjunctivae), such as, for example, allergic conjunctivitis andallergic rhinitis; disorders of the arthritis type (for examplerheumatoid arthritis); autoimmune disorders, such as multiple sclerosis;furthermore periodontitis, anaphylaxis, interstitial cystitis,dermatitis, psoriasis, sclerodermia/systemic sclerosis, inflammatoryintestinal disorders (Crohns disease, inflammatory bowel disease) andothers. In particular, tryptase seems to be connected directly to thepathogenesis of asthma (Caughey, Am. J. Respir. Cell Mol. Biol. 16(1997), 621-628; R. Tanaka, “The role of tryptase in allergicinflammation” in: Protease Inhibitors, IBC Library Series, 1979, Chapter3.3.1-3.3.23).

A further subject of the invention relates to the compounds according tothe invention for use in the treatment and/or prophylaxis of diseases,in particular the diseases mentioned.

The invention likewise relates to the use of the compounds according tothe invention for preparing medicaments which are employed for thetreatment and/or prophylaxis of the diseases mentioned.

Medicaments for the treatment and/or prophylaxis of the diseasesmentioned, which contain one or more of the compounds according to theinvention, are furthermore subject of the invention.

The medicaments are prepared by processes which are known per se to theperson skilled in the art. As medicaments, the compounds according tothe invention (=active compounds) are either employed as such, orpreferably in combination with suitable pharmaceutical excipients, forexample in the form of tablets, coated tablets, capsules, suppositories,patches, emulsions, suspensions, gels or solutions, the active compoundcontent advantageously being between 0.1 and 95%.

The person skilled in the art is familiar on the basis of his/her expertknowledge with the excipients which are suitable for the desiredpharmaceutical formulations. In addition to solvents, gel-formingagents, ointment bases and other active compound vehicles, it ispossible to use, for example, antioxidants, dispersants, emulsifiers,preservatives, solubilizers or permeation promoters.

For the treatment of disorders of the respiratory tract, the compoundsaccording to the invention are preferably also administered byinhalation. For this purpose, they are either administered directly as apowder (preferably in micronized form) or by nebulization of solutionsor suspensions which contain them. With respect to the preparations andadministration forms, reference is made, for example, to the details inEuropean patent 163 965.

For the treatment of dermatoses, the compounds according to theinvention are in particular used in the form of those medicaments whichare suitable for topical administration. For the preparation of themedicaments, the compounds according to the invention (=activecompounds) are preferably mixed with suitable pharmaceutical excipientsand further processed to give suitable pharmaceutical formulations.Suitable pharmaceutical formulations which may be mentioned are, forexample, powders, emulsions, suspensions, sprays, oils, ointments, fattyointments, creams, pastes, gels or solutions.

The medicaments according to the invention are prepared by processesknown per se. The dosage of the active compounds in the case of systemictherapy (p.o. or i.v.) is between 0.1 and 10 mg per kilogram and day.

Biological Investigations

The documented pathophysiological effects of mast cell tryptase arebrought about directly by the enzymic activity of the protease.Accordingly, they are reduced or blocked by inhibitors which inhibit theenzymatic activity of the tryptase. The equilibrium dissociationconstant K_(i) of the enzyme-inhibitor complex is a suitable measure ofthe affinity of a reversible inhibitor for the target protease. ThisK_(i) value can be determined by measuring the effect of the inhibitoron the tryptase-induced cleavage of a chromogenic peptide-p-nitroanilidesubstrate or a fluorogenic peptide-aminomethylcoumarin substrate.

Methodology

The dissociation constants of the tryptase-inhibitor complexes aredetermined under equilibrium conditions in accordance with the generalrecommendations of Bieth (Bieth J G, Pathophysiological interpretationof kinetic constants of protease inhibitors, Bull. Europ. Physiopath.Resp. 16:183-195, 1980) and the methods of Sommerhoff et al. (SommerhoffC P et al., A. Kazal-type inhibitor of human mast cell tryptase:Isolation from the medical leech Hirudo medicinalis, characterization,and sequence analysis, Biol. Chem. Hoppe-Seyler 375: 685-694, 1994).

Human tryptase is prepared in a pure state from lung tissue; thespecific activity of the isolated protease, determined by means oftitration, is normally 85% of the theoretical value. Constant quantitiesof tryptase are incubated with increasing quantities of the inhibitorsin the presence of 50 μg of heparin/ml for stabilizing the protease.After the equilibrium has been established between the reactionpartners, the remaining enzyme activity is determined after adding thepeptide-p-nitroanilide substrate tos-Gly-Pro-Arg-pNA, the cleavage ofwhich is monitored at 405 nm over a period of 3 min. Alternatively, theresidual enzymic activity can also be determined using fluorogenicsubstrates. The apparent dissociation constants K_(iapp) (i.e. in thepresence of substrate) are subsequently ascertained by nonlinearregression by fitting the enzyme rates to the general equation forreversible inhibitors (Morrison J F, Kinetics of the reversibleinhibition of enzyme-catalysed reactions by tight-binding inhibitors,Biochim. Biophys. Acta 185, 269-286, 1969):

V ₁ /V ₀=1−{E _(t) +l _(t) +K _(iapp)−[(E _(t) +l _(t) +K _(iapp))²−4E_(t) l _(t)]^(½)}/2E _(t)

In this equation, V₁ and V₀ are the rates in the presence and absence ofthe inhibitor, respectively, and E_(t) and l_(t) are the concentrationsof the tryptase and of the inhibitor.

The apparent dissociation constants which were determined for thecompounds according to the invention are given in Table A below, inwhich the numbers of the compounds correspond to the numbers of thecompounds in the examples.

TABLE A Inhibition of human tryptase Compound K_(iapp) (μM) 1 3 11 0.0315 3 17 22 21 0.1 23 0.8 31 0.2 34 2 36 0.028

What is claimed is:
 1. A compound of formula I

in which A1 and A2 are each independently selected from the groupconsisting of —O— or —NH—C(O)—, A3 and A4 are each independentlyselected from the group consisting of —C(O)—NH— or

where W is the group —C(O)— or a bond, A5 and A6 are each independentlyselected from the group consisting of —C(O)—, —C(O)—NH—, —NH—C(O)— or abond, M is selected from one of the following groups

K1 is -B7-(C(O))_(m)-B9-X1 or -B7-(C(O))_(m)-B9-Z1-B11-X1, K2 is-B8-(C(O))_(p)-B10-X2 or -B8-(C(O))_(p)-B10-Z2-B12-X2 B1, B2, B3, B4, B5and B6 are each independently selected from the group consisting of abond or —CH₂—, B7, B8, B9, B10, B11 and B12 are each independentlyselected from the group consisting of a bond or 1-2C-alkylene, m is 0 or1, p is 0 or 1, X1 and X2 are each independently selected from the groupconsisting of amino, amidino or guanidino, Z1 and Z2 are eachindependently selected from the group consisting of 1,4-phenylene,1,3-phenylene, 1,4-cyclohexylene or 1,4-piperazinylene, and in which 24to 40 bonds must be present on the direct route between the terminalnitrogen atoms, and A pharmaceutically acceptable salt of said compoundwith all those compounds being excluded in which at least one to twelveof the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 isa bond resulting in the direct linkage of two heteroatoms or twocarbonyl groups.
 2. A compound of claim 1, wherein A5 and A6 are eachindependently selected from the group consisting of —C(O)—, —NH—C(O)— ora bond, M is selected from one of the following groups

 wherein K1 is -B7-(C(O))_(m)-B9-Z1-B11-X1, K2 is -B8-(C(O))_(p)-B10-Z2-B12-X2, B1, B2, B3, B4, B5 and B6 are each independently selectedfrom the group consisting of a bond or —CH₂—, and B7, B8, B9, B10, B11and B12 are each independently selected from the group consisting of abond or —CH₂—.
 3. A compound of claim 1, wherein the compound is:bis{4-[4-(4-aminomethylcyclohexanoyl)piperazin-1-yl]carbonyl}-4,4′-diaminodiphenylether,bis{4-[4-(3-aminomethyl)benzoylpiperazin-1-yl]carbonyl}-4,4′-diaminodiphenylether, di{4-[4-(4-aminomethyl)cyclohexanoylamino]piperidin-1-ylcarbamoyl}cyclohexylmethane,2,2-bis[4-(4-guanidinylbenzylamino)carbonylmethoxyphenyl}propane,2,2-bis[4-(10-amino-3,6-diaza-2,5-dioxodecyloxyphenyl]propane or2,2-bis{4-[4-(4-aminomethylbenzylcarbamoyl)-1-piperazinylcarbonyloxy]phenyl}propane,or a salt thereof.
 4. A method of treating a disease susceptible totryptase inhibition, said method comprising administering to a patientafflicted with such a disease a tryptase inhibiting amount of a compoundof formula I.
 5. A method according to claim 4, wherein the diseasesusceptible to tryptase inhibition is asthma.
 6. A method according toclaim 4, wherein the disease susceptible to tryptase inhibition isinflammatory bowel disease.
 7. A method according to claim 4, whereinthe disease susceptible to tryptase inhibition is psoriasis.
 8. A methodaccording to claim 4, wherein the disease susceptible to tryptaseinhibition is rhinitis.
 9. A method of producing a medicament for thetreatment of respiratory disorders comprising: combining the compound ofclaim 1 with one or more suitable pharmaceutical excipients, wherein thecompound of formula I is in an amount effective to treat respiratorydisorders.
 10. A pharmaceutical composition suitable for treatingrespiratory diseases comprising the compound of claim 1 in an amounteffective to treat respiratory disorders and a pharmaceutical excipient.